Piperazine derivatives

ABSTRACT

A piperazine compound of the formula: ##STR1## wherein: X is carbonyl or sulfonyl; 
     Y is a direct bond or lower alkylene; and 
     R 1 , R 2 , R 3 , R 4  are as defined herein. The compounds are advantageously used as Tachykinin antagonists in the treatment of respiratory diseases, ophthalmic diseases and inflammatory diseases, for example.

This application is a continuation of application Ser. No. 08/450,176,filed on May 25, 1995, now abandoned; which is a continuation in part ofSer. No. 08/348,176, filed Nov. 28, 1994, now U.S. Pat. No. 5,670,505.

The present invention relates to new piperazine derivatives and apharmaceutically acceptable salt thereof.

More particularly, it relates to new piperazine derivatives and apharmaceutically acceptable salt thereof which have pharmacologicalactivities such as Tachykinin antagonism, especially Substance Pantagonism, Neurokinin A antagonism, Neurokinin B antagonism, and thelike, to a process for preparation thereof, to a pharmaceuticalcomposition comprising the same, and to a use of the same as amedicament.

Accordingly, one object of the present invention is to provide new anduseful piperazine derivatives and a pharmaceutically acceptable saltthereof which have pharmacological activities such as Tachykininantagonism, especially Substance P antagonism, Neurokinin A antagonism,Neurokinin B antagonism, and the like.

Another object of the present invention is to provide a process for thepreparation of said piperazine derivatives and a salt thereof.

A further object of the present invention is to provide a pharmaceuticalcomposition comprising, as an active ingredient, said piperazinederivatives and a pharmaceutically acceptable salt thereof.

Still further object of the present invention is to provide a use ofsaid piperazine derivatives or a pharmaceutically acceptable saltthereof as Tachykinin antagonist, especially Substance P antagonist,Neurokinin A antagonist or Neurokinin B antagonist, useful for treatingor preventing Tachykinin-mediated diseases, for example, respiratorydiseases such as asthma, bronchitis, rhinitis, cough, expectoration, andthe like; ophthalmic diseases such as conjunctivitis, vernalconjunctivitis, and the like; cutaneous diseases such as contactdermatitis, atopic dermatitis, urticaria, and other eczematoiddermatitis, and the like; inflammatory diseases such as rheumatoidarthritis, osteoarthritis, and the like; pains or aches (e.g., migraine,headache, toothache, cancerous pain, back pain, etc.); and the like inhuman being or animals.

The object compound of the present invention can be represented by thefollowing general formula (I): ##STR2## wherein X is carbonyl orsulfonyl;

Y is bond or lower alkylene;

R¹ is halogen, lower alkyl, halo(lower)alkyl, aryloxy, nitro or aminowhich may have 1 or 2 and same or different substituent(s) selected fromlower alkyl, acyl and lower alkanesulfonyl;

R² is aryl or an aromatic hetero(mono- or bi-)cyclic group, and each ofwhich may have 1, 2 or 3 suitable substituent(s);

R³ is hydrogen or lower alkyl;

R⁴ is

(i) a group of the formula --SO₂ --R⁵

in which R⁵ is lower alkyl or aryl optionally substituted with loweralkyl or lower alkoxy,

(ii) a group of the formula ##STR3## in which R⁶ is aryl optionallysubstituted with lower alkyl or lower alkoxy, or

(iii) a group of the formula --A--(Z)p

in which

A is bond, lower alkylene, lower alkenylene or lower alkynylene,

Z is hydrogen, halogen, hydroxy, nitrile, amino, cyclo(lower)alkyl,aryl, aryloxy, acyl, acylamino, lower alkanesulfonylamino,arylsulfonylamino or an aromatic hetero(mono- or bi-)cyclic group, andeach of the cyclic group may have 1, 2 or 3 suitable substituent(s), andp is 1, 2 or 3; and

n is 0, 1 or 2;

provided that when n or p is more than 1, these R¹ and Z may be the sameor different group respectively;

or its pharmaceutically acceptable salt.

According to the present invention, the object compound (I) or a saltthereof can be prepared by processes which are illustrated in thefollowing schemes.

Process 1 ##STR4## Process 2 ##STR5## Process 3 ##STR6## Process 4##STR7## Process 5 ##STR8## Process 6 ##STR9## Process 7 ##STR10##wherein X, Y, Z, R¹, R², R³, R⁴, n and p are each as defined above;

X¹ is carboxy or its reactive derivative, or sulfo or its reactivederivative;

X² is a leaving group;

R_(a) ² is lower alkyl;

R_(a) ⁴ is an imino-protective group;

R_(c) ⁴ is

(i) a group of the formula --SO₂ --R⁵

in which R⁵ is lower alkyl or aryl optionally substituted with loweralkyl or lower alkoxy,

(ii) a group of the formula ##STR11## in which R⁶ is aryl optionallysubstituted with lower alkyl or lower alkoxy, or

(iii) acyl;

R_(d) ⁴ and R_(e) ⁴ are independently hydrogen or an organic group, orR_(d) ⁴ and R_(e) ⁴ together with the nitrogen atom form a N containingsaturated heterocyclic group which may be substituted by 1 to 3 and sameor different suitable substituent(s);

R_(f) ⁴ is lower alkyl or ar(lower)alkyl;

A₁ is lower alkylene, lower alkenylene or lower alkynylene; and

W is a leaving group.

As to the starting compounds (II), (III), (IV), (V), (VI) and (VII),some of them are novel and can be prepared by the procedures describedin the Preparations and Examples mentioned later or a conventionalmanner.

Throughout the present specification, the amino acid, peptides,protective groups, condensing agents, etc. are expressed by theabbreviations according to the IUPAC-IUB (Commission on BiologicalNomenclature) which are in common use in the field of this art.

Suitable salts and pharmaceutically acceptable salts of the starting andobject compounds are conventional nontoxic salt and include an acidaddition salt such as an organic acid salt (e.g. acetate,trifluoroacetate, fumarate, maleate, tartrate, methanesulfonate,benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acidsalt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate,phosphate, etc.), or a salt with an amino acid (e.g. arginine, asparticacid, glutamic acid, etc.), or a metal salt such as an alkali metal salt(e.g. sodium salt, potassium salt, etc.) and an alkaline earth metalsalt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, anorganic base salt (e.g. trimethylamine salt, triethylamine salt,pyridine salt, picoline salt, dicyclohexylamine salt,N,N'-dibenzylethylenediamine salt, etc.), or the like.

In the above and subsequent descriptions of the present specification,suitable examples and illustrations of the various definitions which thepresent invention include within the scope thereof are explained indetail as follows.

The term "lower" is intended to mean 1 to 6, preferably 1 to 4 carbonatom(s), unless otherwise indicated.

Suitable "lower alkylene" is straight or branched one having 1 to 6carbon atom(s) and may include methylene, ethylene, trimethylene,propylene, tetramethylene, methylmethylene, methyltrimethylene,hexamethylene, and the like, in which the preferred one is methylene,ethylene, trimethylene or methylmethylene.

The term "lower alkenylene" means one having one or two double bond(s)in the straight or branched lower alkylene group as defined above.

Suitable "lower alkenylene" may include one having 2 to 6 carbon atomssuch as vinylene, 1-propenylene, 2-propenylene, 1,3-butadienylene,1-methylvinylene, etc.

Suitable "lower alkynylene" may include one having 2 to 6 carbon atomssuch as ethynylene, propynylene, 2-penten-4-ynylene, etc.

The term "halogen" is fluoro, chloro, bromo and iodo. Suitable "loweralkyl" is straight or branched one having 1 to 6 carbon atom(s) and mayinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyland the like.

Suitable "halo(lower)alkyl" may include chloromethyl, bromomethyl,fluoromethyl, iodomethyl, trifluoromethyl, dichloromethyl,2-fluoroethyl, 1-chloroethyl, 2-chloroethyl and the like, in which thepreferred one is trifluromethyl.

Suitable "cyclo(lower)alkyl" may include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like.

Suitable "aryl" may include phenyl, tolyl, xylyl, mesityl, cumenyl,biphenylyl, naphthyl, and the like, in which the preferred one is C₆-C₁₀ aryl and the most preferred one is phenyl.

Suitable "aryloxy" may include phenoxy, tolyloxy, naphthyloxy and thelike.

Suitable "aromatic hetero(mono- or bi-)cyclic group" may includeunsaturated monocyclic or bicyclic heterocyclic group containing atleast one hetero atom such as nitrogen, oxygen and sulfur atoms.

Preferable "aromatic hetero(mono)cyclic group" may include 5- or6-membered aromatic hetero(mono)cyclic group containing one to fourhetero atoms selected from nitrogen, oxygen and sulfur atoms and may beexemplified pyrrolyl, pyridyl, furyl, thienyl, oxazolyl, isooxazolyl,thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl,pyrazinyl, pyridazinyl and the like.

Preferable "aromatic hetero(bi)cyclic group" may include condensedaromatic heterocyclic group containing one, two or three hetero atomsselected from nitrogen, oxygen and sulfur atoms and may be exemplifiedbenzothienyl, phthalimido, benzofuranyl, indolyl, indolizinyl,isoindolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, phthalazinyl,quinazolinyl, cinnolinyl, benzoisoxazolyl and the like.

The "aromatic hetero(mono- or bi-)cyclic group" in the definition of R²or Z may be bonded to the adjacent "Y" or "A" in the formula (I) at thecarbon atom or the hetero atom in the heterocyclic ring.

The "aryl" and "aromatic hetero(mono- or bi-)cyclic group" in thedefinition of R² may be substituted by 1 to 3 and same or differentsuitable substituent(s).

Suitable substituents of the "aryl or an aromatic hetero(mono- orbi-)cyclic group" for R² may include lower alkyl, halogen,halo(lower)alkyl, oxo, amino, lower alkanoylamino (e.g., formylamino,acetylamino, etc.), (mono- or di-)lower alkylamino(lower)alkyl (e.g.,2-dimethylaminoethyl, etc.) and the like.

More preferable "aromatic hetero(mono- or bi-)cyclic group which mayhave 1, 2 or 3 suitable substituent(s)" may include 1H-1-(loweralkyl)indol-3-yl and the like.

Suitable "lower alkoxy" may include methoxy, ethoxy, isopropyloxy,butoxy and the like.

The "aryl" in the definition of R⁵ and R⁶ may be substituted by 1 to 3and same or different substituent(s) selected from lower alkyl asdefined above and lower alkoxy as defined above.

Suitable "lower alkanesulfonylamino" may include mesylamino,ethanesulfonylamino and the like.

Suitable "arylsulfonylamino" may include phenylsulfonylamino,naphthylsulfonylamino and the like.

The "amino" in the definition of R¹ may have 1 or 2 and same ordifferent substituent(s) selected from lower alkyl as defined above,lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, and the like) andacyl as defined below (e.g., lower alkanoyl and the like).

Preferable "amino which may have 1 or 2 and same or differentsubstituent(s)" may be exemplified methylamino, dimethylamino,formylamino, acetylamino, N-formyl-N-methylamino, mesylamino, and thelike.

In the definition of "Z", the "cyclic group" such as "cyclo(lower)alkyl,aryl, aryloxy, arylsulfonylamino or an aromatic hetero(mono- orbi-)cyclic group" may have 1, 2 or 3 and same or different suitablesubstituent(s).

Preferable substituents of the "cyclic group" in the definition of "Z"may include halogen, lower alkyl, halo(lower)alkyl, lower alkoxy, loweralkanesulfonyl, lower alkanesulfonylamino and arylsulfonylamino as eachas defined above, hydroxy, nitro, lower alkanoylamino, cyano, amino,acyl as defined below (e.g., carboxy, lower alkoxycarbonyl, carbamoyl,(mono- or di-)lower alkylcarbamoyl, lower alkanoyl, etc.), acylamino asdefined below (e.g., lower alkanoylamino such as acetylamino, etc.),(mono- or di-)lower alkylamino (as described below),N-(lower)alkanoyl-N-(lower)alkylamino (e.g., N-acetyl-N-methylamino,N-propionyl-N-methylamino, etc.), and the like.

Suitable "acyl moiety" for the "acyl group and acylamino group" in thedefinition of "Z" may include an aliphatic acyl group, an aromatic acylgroup and a saturated heterocyclic carbonyl group and each of which maybe substituted by 1 to 3 and same or different suitable substituent(s).

Suitable example of said acyl moiety may include:

(a) aliphatic acyl group

(a-1) optionally substituted carboxy or esterified carboxy group

Preferable "ester moiety" in the term of "esterified carboxy group"includes the ones such as lower alkyl ester (e.g., methyl ester, ethylester, propyl ester, isopropyl ester, butyl ester, isobutyl ester,t-butyl ester, etc.), lower alkenyl ester (e.g., vinyl ester, allylester, etc.), lower alkynyl ester (e.g., ethynyl ester, propynyl ester,etc.), and the like, and each of which may be substituted by an arylwhich may further be substituted by 1 to 3 and same or differentsubstituent(s) selected from the "Substituent list M" as describedbelow.

(a-2) optionally substituted lower alkanoyl group

Preferable lower alkanoyl group includes formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc. and each ofwhich may have 1 to 3 and same or different substituent(s) selected fromthe "Substituent list Q" as described below.

(a-3) optionally substituted cyclo(lower)alkylcarbonyl group

Preferable cyclo(lower)alkylcarbonyl group includes cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc. andeach of which may have 1 to 3 and same or different substituent(s)selected from the "Substituent list M" as described below.

(a-4) optionally substituted lower alkenoyl group

Preferable lower alkenoyl group includes acryloyl, methacryloyl,crotonoyl, isocrotonoyl, etc. and each of which may have 1 to 3 and sameor different substituent(s) selected from the "Substituent list Q" asdescribed below.

(a-5) optionally substituted lower alkynoyl group

Preferable lower alkynoyl group includes ethynylcarbonyl,propynylcarbonyl, etc. and each of which may have 1 to 3 and same ordifferent substituent(s) selected from the "Substituent list Q" asdescribed below.

(a-6) carbamoyl derivative illustrated by the formula: ##STR12##(wherein R_(d) ⁴ and R_(e) ⁴ are independently hydrogen or an organicgroup, or R_(d) ⁴ and R_(e) ⁴ together with the nitrogen atom form a "Ncontaining saturated heterocyclic group" which may be substituted by 1to 3 and same or different substituent(s) selected from the "Substituentlist M" as stated below).

Preferable "organic group" for R_(d) ⁴ and R_(e) ⁴ is lower alkyl whichmay be substituted by a group selected from the "Substituent list Q" ora group selected from the "Substituent list Q" as stated below.

Preferable "carbamoyl derivative" includes carbamoyl group, lower alkylcarbamoyl group (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), di-(loweralkyl)carbamoyl group (e.g., dimethylcarbamoyl, diethylcarbamoyl, etc.),and a group of the formula: ##STR13## (wherein ##STR14## is a Ncontaining saturated heterocyclic group and R_(g) ⁴ is hydrogen or anorganic group).

Preferable "organic group" for R_(g) ⁴ is a group selected from the"Substituent list M" as defined below.

More preferable "N containing saturated heterocyclic group" for##STR15## may include 5-, 6- or 7-membered heterocyclic group whichcontains at least one nitrogen atom as a hetero atom. Most preferableone is 1-pyrrolidinyl, 1-piperidyl, 4-morpholino, 1-piperazinyl,1-homopiperazinyl, etc., and the heterocyclic group may be substitued by1 to 3 and same or different substituent(s) selected from the"Substituent list M" as defined below.

(b) aromatic acyl group

(b-1) optionally substituted aroyl group

Preferable "aroyl group" includes benzoyl, toluoyl, naphthoyl, etc.

The aroyl group may be substituted by 1 to 3 and same or differentsubstituent(s) selected from the "Substituent list M" as describedbelow.

(b-2) optionally substituted aromatic hetero(mono- or bi-)cycliccarbonyl group

Preferable "aromatic hetero(mono- or bi-)cyclic group moiety" in the"aromatic hetero(mono- or bi-)cyclic carbonyl group" is the one asexemplified before.

The "aromatic hetero(mono- or bi-)cyclic carbonyl group" may besubstituted by 1 to 3 and same or different substituent(s) selected fromthe "Substituent list M" as described below.

(c) optionally substituted saturated heterocyclic carbonyl group

Preferable "saturated heterocyclic group moiety" in the "saturatedheterocyclic carbonyl group" may include 5- or 6-membered heterocyclicgroup which contains at least one nitrogen atom as a hetero atom. Mostpreferable one is pyrrolidinyl, piperidyl, piperazinyl, etc. and theheterocyclic group may have 1 to 3 and same or different substituent(s)selected from the "Substituent list M" as described below.

Substituent list M

aryl; aroyl; aryloxy; lower alkyl optionally substituted by hydroxy;ar(lower)alkyl; carbamoyl; cyclo(lower)alkyl; carboxy; cyano; halogen;hydroxy; lower alkanoyl; lower alkanoyloxy; lower alkoxy; aminooptionally substituted by 1 or 2 and same or different substituent(s)selected from lower alkyl, aryl, lower alkanoyl, lower alkanesulfonyland aroyl; oxo; nitro; lower alkoxycarbonyl; N containing saturatedheterocyclic group; or aromatic hetero(mono- or bi-)cyclic group.

Substituent list Q

aryl optionally substituted by 1 or 2 of amino, halogen, hydroxy, nitro,halo(lower)alkyl, lower alkoxy, lower alkyl, lower alkanoylamino or(mono- or di-)lower alkylamino; aryloxy; aroyl; lower alkoxy; halogen;hydroxy; carbamoyl; lower alkoxycarbonyl which may be substituted byaryl; amino optionally substituted by 1 or 2 and same or differentsubstituent(s) selected from lower alkyl, aryl, lower alkanoyl, loweralkanesulfonyl and aroyl; ureido; N containing saturated heterocyclicgroup optionally substituted by lower alkyl, aryl or loweralkanoylamino; carboxy; cyclo(lower)alkyl; or aromatic hetero(mono- orbi-)cyclic group optionally substituted by amino, lower alkyl or loweralkanoylamino.

In the explanation of the above lists of substituent(s), suitableexamples and illustrations of the each definitions are the same orequivalent one which are beforementioned, or the one described below:

"(mono- or di-)lower alkylamino" may include lower alkylamino anddi(lower alkyl)amino.

suitable "lower alkylamino" may include straight or branched loweralkylamino such as methylamino, ethylamino, isopropylamino, etc., andthe lower alkyl moiety may be substituted by 1 to 3 and same ordifferent another substituent(s) selected from the "Substituent list Q",wherein more preferable lower alkylamino is methylamino and benzylamino,

suitable "di(lower alkyl)amino" may include straight or brancheddi(lower alkyl)amino such as dimethylamino, diethylamino,methylethylamino, etc., and the lower alkyl moiety may be substituted by1 to 3 and same or different another substituent(s) selected from the"Substituent list Q", wherein more preferable di(lower alkyl)amino isdimethylamino and N-methyl-N-benzylamino, etc.,

suitable "lower alkoxycarbonyl" may include methoxycarbonyl,ethoxycarbonyl, t-butoxycarbonyl, etc.

More preferable compounds of this invention may include the one havingthe following definition in the general formula (I),

X is carbonyl;

Y is lower alkylene;

R¹ is halo(lower)alkyl, halogen or amino;

R² is an aromatic hetero(bi-)cyclic group;

R³ is hydrogen;

R⁴ is a group of the formula --A--Z in which A is lower alkylene and Zis acyl; and

n is 1 or 2;

or its pharmaceutically acceptable salt.

In the above definitions, each definition is the same as defined above,and acyl moiety for "Z" may include carbamoyl derivatives illustrated bythe formula: ##STR16## wherein R_(d) ⁴ and R_(e) ⁴ are the same asdefined above.

Most preferable "acyl moiety" in the definition of "Z" is a group of theformula: ##STR17## wherein ##STR18## and R_(g) ⁴ are the same as definedabove.

New piperazine derivatives of this invention may include the one havingthe following definition in the general formula (I),

X is carbonyl;

Y is lower alkylene;

R¹ is halo(lower)alkyl;

R² is an aromatic hetero(bi-)cyclic group;

R³ is hydrogen;

R⁴ is a group of the formula --A--Z

in which

A is bond or lower alkylene and

Z is acyl or aromatic hetero(mono- or bi-)cyclic group and each of thecyclic group may have 1, 2 or 3 suitable substituent(s); and

n is 1 or 2;

or its pharmaceutically acceptable salt.

In the above definitions, each definition is the same as defined above.

Suitable "leaving group" may include hydroxy, reactive group derivedfrom hydroxy and the like.

Suitable "reactive group derived from hydroxy" may include acid residueand the like.

Suitable "acid residue" may include halogen (e.g. fluoro, chloro, bromo,iodo), acyloxy (e.g. acetoxy, tosyloxy, mesyloxy, etc.) and the like.

Suitable "imino-protective group" may include ar(lower)alkyl such asbenzyl, benzhydryl, phenethyl and the like.

The Processes 1 to 7 for preparing the object compound (I) of thepresent invention are explained in detail in the following.

Process 1

The object compound (I) or a salt thereof can be prepared by reacting acompound (II) or a salt thereof with a compound (III) or its reactivederivative at the imino group or a salt thereof.

Suitable reactive derivative at the imino group of the compound (III)may include Schiff's base type imino or its tautomeric enamine typeisomer formed by the reaction of the compound (III) with a carbonylcompound such as aldehyde, ketone or the like; a silyl derivative formedby the reaction of the compound (III) with a silyl compound such asbis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide,bis(trimethylsilyl)urea or the like; a derivative formed by reaction ofthe compound (III) with phosphorus trichloride or phosgene and the like.

Suitable reactive derivative at the carboxy group and the sulfo group ofthe compound (II) may include an acid halide, an acid anhydride, anactivated amide, an activated ester, lower alkyl ester, and the like.Suitable examples of the reactive derivatives may be an acid chloride;an acid azide; a mixed acid anhydride within acid such as substitutedphosphoric acid e.g. dialkylphosphoric acid, phenylphosphoric acid,diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoricacid, etc.!, dialkylphosphorous acid, sulfurous acid, thiosulfuric acid,sulfuric acid, sulfonic acid e.g. methanesulfonic acid, etc.!, aliphaticcarboxylic acid e.g. acetic acid, propionic acid, butyric acid,isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, etc.! or aromatic carboxylicacid e.g. benzoic acid, etc.!; a symmetrical acid anhydride; anactivated amide with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole or tetrazole; or an activated ester e.g.cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ##STR19##ester, vinyl ester, propargyl ester, p-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,mesylphenyl ester, phenylazophenyl ester, phenyl thioester,p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester,pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester,etc.!, or an ester with a N-hydroxy compound e.g.N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole,etc.!, and the like. These reactive derivatives can optionally beselected from the above according to the kind of the compound (II) to beused.

The reaction is usually carried out in a conventional solvent such aswater, alcohol e.g. methanol, ethanol, etc.!, acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvent may also be used in a mixture with water.

In this reaction, when the compound (II) is used in a free acid form orits salt form, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide;N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride);phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride;oxalyl chloride; lower alkyl haloformate e.g. ethyl chloroformate,isopropyl chloroformate, etc.!; triphenylphosphine;2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxaozlium hydroxide intramolecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole;2-chloro-1-methylpyridinium iodide;1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, trichloromethyl chloroformate, phosphorusoxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic ororganic base such as an alkali metal bicarbonate, tri(lower)alkylamine,pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, orthe like.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to warming.

Process 2

The object compound (Ia) or a salt thereof can be prepared by subjectingthe compound (Iz) or a salt thereof to elimination reaction of theimino-protective group.

In the present elimination reaction, all conventional methods used inthe elimination reaction of the imino-protective group, for example,hydrolysis, reduction, elimination using base or acid, etc. areapplicable.

Suitable base may include, for example, an inorganic base such as alkalimetal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.),alkaline earth metal hydroxide (e.g. magnesium hydroxide, calciumhydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate,potassium carbonate, etc.), alkaline earth metal carbonate (e.g.magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate(e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metalacetate (e.g. sodium acetate, potassium acetate, etc.), alkaline earthmetal phosphate (e.g. magnesium phosphate, calcium phosphate, etc.),alkali metal hydrogen phosphate (e.g. disodium hydrogen phosphate,dipotassium hydrogen phosphate, etc.), or the like, and an organic basesuch as trialkylamine (e.g. trimethylamine, triethylamine, etc.),picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo4.3.0!non-5-ene, 1,4-diazabicyclo 2.2.2!octane, 1,5-diazabicyclo5.4.0!undecene-5 or the like. The hydrolysis using a base is oftencarried out in water or a hydrophilic organic solvent or a mixed solventthereof.

Suitable acid may include an organic acid (e.g. formic acid, aceticacid, propionic acid, etc.) and an inorganic acid (e.g. hydrochloricacid, hydrobromic acid, sulfuric acid, etc.).

The present hydrolysis is usually carried out in an organic solvent,water or a mixed solvent thereof.

The reaction temperature is not critical, and it may suitably beselected in accordance with the kind of the imino-protective group andthe elimination method.

The elimination using Lewis acid is preferable to eliminate substitutedor unsubstituted ar(lower)alkyl ester and carried out by reacting thecompound (Iz) or a salt thereof with Lewis acid such as boron trihalide(e.g. boron trichloride, boron trifluoride, etc.), titanium tetrahalide(e.g. titanium tetrachloride, titanium tetrabromide, etc.), tintetrahalide (e.g. tin tetrachloride, tin tetrabromide, etc.), aluminumhalide (e.g. aluminum chloride, aluminum bromide, etc.), trihaloaceticacid (e.g. trichloroacetic acid, trifluoroacetic acid, etc.) or thelike. This elimination reaction is preferably carried out in thepresence of cation trapping agents (e.g. anisole, phenol, etc.) and isusually carried out in a solvent such as nitroalkane (e.g. nitromethane,nitroethane, etc.), alkylene halide (e.g. methylene chloride, ethylenechloride, etc.), diethyl ether, carbon disulfide or any other solventwhich does not adversely affect the reaction. These solvents may be usedas a mixture thereof.

The reduction elimination can be applied preferably for elimination ofthe protective group such as halo(lower)alkyl (e.g. 2-iodoethyl,2,2,2-trichloroethyl, etc.) ester, ar(lower)alkyl (e.g. benzyl, etc.)ester or the like.

The reduction method applicable for the elimination reaction mayinclude, for example, reduction by using a combination of a metal (e.g.zinc, zinc amalgam, etc.) or a salt of chromium compound (e.g. chromouschloride, chromous acetate, etc.) and an organic or an inorganic acid(e.g. acetic acid, propionic acid, hydrochloric acid, etc.); andconventional catalytic reduction in the presence of a conventionalmetallic catalyst (e.g. palladium carbon, Raney nickel, etc.).

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling, at ambient temperature or under warming.

Process 3

The object compound (Ib) or a salt thereof can be prepared by reactingthe compound (Ia) or its reactive derivative at the imino group or asalt thereof with the compound (V) or a salt thereof.

Suitable example of the reactive derivative at the imino group of thecompound (Ia) is the one as exemplified for compound (III) in theProcess 1.

This reaction is usually carried out in a solvent such as alcohol e.g.methanol, ethanol, etc.!, dichloromethane, benzene,N,N-dimethylformamide, tetrahydrofuran, diethyl ether or any othersolvent which does not adversely affect the reaction.

The reaction may be carried out in the presence of an inorganic or anorganic base such as an alkali metal hydroxide e.g. sodium hydroxide,potassium hydroxide, etc.!, an alkali metal carbonate e.g. sodiumcarbonate, potassium carbonate, etc.!, an alkali metal bicarbonate e.g.sodium bicarbonate, potassium bicarbonate, etc.!, alkali metal hydridee.g. sodium hydride, potassium hydride, etc.!, tri(lower)alkylamine e.g.trimethylamine, triethylamine, diisopropylethylamine, etc.!, pyridine orits derivative e.g. picoline, lutidine, 4-dimethylaminopyridine, etc.!,or the like. In case that the base to be used in liquid, it can also beused as a solvent.

The reaction temperature is not critical, and the reaction can becarried out under cooling, at room temperature or under warming orheating.

Process 4

The object compound (Ic) or a salt thereof can be prepared by reactingthe compound (Ia) or its reactive derivative at the imino group or asalt thereof with the compound (VI) or a salt thereof.

Suitable example of the reactive derivative at the imino group of thecompound (Ia) is the one as exemplified in the Process 1.

This reaction can be carried out in substantially the same manner as theProcess 1, and therefore the reaction mode and reaction conditions e.g.solvents, reaction temperature, etc.! of this reaction are to bereferred to those as explained in the Process 1.

Process 5

The compound (Ie) or a salt thereof can be prepared by reacting acompound (Id) or its reactive derivative at the carboxy group or a saltthereof with a compound (IV) or a salt thereof.

Suitable example of the reactive derivative at the carboxy group of thecompound (Id) is the one as exemplified for compound (II) in the Process1.

This reaction can be carried out in substantially the same manner as theProcess 1, and therefore the reaction mode and reaction conditions e.g.solvents, reaction temperature, etc.! of this reaction are to bereferred to those as explained in the Process 1.

Process 6

The compound (Ig) or a salt thereof can be prepared by subjecting acompound (If) or a salt thereof to deesterification reaction.

The reaction is carried out in accordance with a conventional methodsuch as hydrolysis, reduction or the like.

The hydrolysis is preferably carried out in the presence of a base or anacid including Lewis acid. Suitable base may include an inorganic baseand an organic base such as an alkali metal e.g. sodium, potassium,etc.!, an alkaline earth metal e.g. magnesium, calcium, etc.!, thehydroxide or carbonate or bicarbonate thereof, trialkylamine e.g.trimethylamine, triethylamine, etc.!, picoline, 1,5-diazabicyclo4.3.0!non-5-ene, 1,4-diazabicyclo 2.2.2!octane, 1,8-diazabicyclo5.4.0!undec-7-ene, or the like. Suitable acid may include an organicacid e.g. formic acid, acetic acid, propionic acid, trichloroaceticacid, trifluoroacetic acid, etc.!, an inorganic acid e.g. hydrochloricacid, hydrobromic acid, hydroiodic acid, sulfuric acid, etc.! and Lewisacid e.g. boron tribromide, etc.!.

The reaction is usually carried out in a solvent such as water, analcohol e.g. methanol, ethanol, etc.!, methylene chloride,tetrahydrofuran, a mixture thereof or any other solvent which does notadversely influence the reaction. A liquid base or acid can be also usedas the solvent. The reaction temperature is not critical, and thereaction can be usually carried out under cooling, at ambienttemperature or under warming.

The reduction can be applied preferably for elimination of the estermoiety such as 4-nitrobenzyl, 2-iodoethyl, 2,2,2-trichloroethyl, or thelike. The reduction method applicable for the elimination reaction mayinclude chemical reduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are acombination of metal e.g. tin, zinc, iron, etc.! or metallic compounde.g. chromium chloride, chromium acetate, etc.! and an organic orinorganic acid e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.!.

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalyst e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.!, palladium catalyst e.g. spongy palladium, palladium black,palladium oxide, palladium on carbon, colloidal palladium, palladium onbarium sulfate, palladium on barium carbonate, etc.!, nickel catalyste.g. reduced nickel, nickel oxide, Raney nickel, etc.!, cobalt catalyste.g. reduced cobalt, Raney cobalt, etc.!, iron catalyst e.g. reducediron, Raney iron, etc.!, copper catalyst e.g. reduced copper, Raneycopper, Ullman copper, etc.! or the like.

The reduction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, an alcohol e.g.methanol, ethanol, propanol, etc.!, N,N-dimethylformamide, or a mixturethereof. Additionally, in case that the above-mentioned acids to be usedin chemical reduction are in liquid, they can also be used as a solvent.Further, a suitable solvent to be used in catalytic reduction may be theabove-mentioned solvent, and other conventional solvent such as diethylether, dioxane, tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature of this reduction is not critical, and thereaction can be usually carried out under cooling, at ambienttemperature or under warming.

Process 7

The object compound (Ii) or a salt thereof can be prepared by reactingthe compound (Ih) or a salt thereof with the compound (VII) or a saltthereof.

This reaction can be carried out in substantially the same manner as theProcess 3, and therefore the reaction mode and reaction conditions e.g.solvents, reaction temperature, etc.! of this reaction are to bereferred to those as explained in the Process 3.

It is to be noted that the compound (I) and the other compounds mayinclude one or more stereoisomers due to asymmetric carbon atoms, andall of such isomers and mixture thereof are included within the scope ofthis invention.

The object compound (I) and a pharmaceutically acceptable salt thereofhave pharmacological activities such as Tachykinin antagonism,especially Substance P antagonism, Neurokinin A antagonism or NeurokininB antagonism, and therefore are useful for treating or preventingTachykinin-mediated diseases, particularly Substance P-mediateddiseases, for example, respiratory diseases such as asthma, bronchitis(e.g. chronic bronchitis, acute bronchitis and diffuse panbronchiolitis,etc.), rhinitis, cough, expectoration, and the like; ophthalmic diseasessuch as conjunctivitis, vernal conjunctivitis, and the like; cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria, andother eczematoid dermatitis, and the like; inflammatory diseases such asrheumatoid arthritis, osteoarthritis, and the like; pains or aches (e.g.migraine, headache, cluster headache, toothache, cancerous pain, backpain, neuralgia, etc.); and the like.

Further, it is expected that the object compound (I) and apharmaceutically acceptable salt thereof of the present invention areuseful for treating or preventing ophthalmic diseases such as glaucoma,uveitis, and the like; gastrointestinal diseases such as ulcer,ulcerative colitis, irritable bowel syndrome, food allergy, and thelike; inflammatory diseases such as nephritis, and the like; circulatorydiseases such as hypertension, angina pectoris, cardiac failure,thrombosis, Raynaud's disease, and the like; epilepsy; spasticparalysis; pollakiuria; cystitis; bladder detrusor hyperreflexia;urinary incontinence; dementia; AIDS related dementia; Alzheimer'sdiseases; Down's syndrome; Huntington's chorea; carcinoid syndrome;disorders related to immune enhancement or suppression; and the like.

It is furthermore expected that the object compound (I) and apharmaceutically acceptable salt thereof of the present invention areuseful for treating or preventing chronic obstructive pulmonarydiseases, particularly chronic pulmonary emphysema; iritis;proliferative vitreoretinopathy; psoriasis; inflammatory intestinaldiseases, particularly Crohn's diseases; hepatitis; superficial pain oncongelation, burn, herpes zoster or diabetic neuropathy; tenalgiaattended to hyperlipidemia; postoperative neuroma, particularly ofmastectomy; vulvar vestibulitis; hemodialysis-associated itching; lichenplanus; laryngopharyngitis; bronchiectasis; coniosis; whooping cough;pulmonary tuberculosis; cystic fibrosis; emesis; mental diseases,particularly anxiety, depression, dysthymic disorders and schizophrenia;demyelinating diseases such as multiple sclerosis and amyotrophiclateral sclerosis; attenuation of morphine withdrawal; oedema, such asoedema caused by thermal injury; small cell carcinomas, particularlysmall cell lung cancer (SCLC); hypersensitivity disorders such as poisonivy; fibrosing and collagen diseases such as scleroderma andeosinophilic fascioliasis; reflex sympathetic dystrophy such asshoulder/hand syndrome; addiction disorders such as alcoholism; stressrelated somatic disorders; rheumatic diseases such as fibrositis; andthe like.

For therapeutic purpose, the compound (I) and a pharmaceuticallyacceptable salt thereof of the present invention can be used in a formof pharmaceutical preparation containing one of said compound, as anactive ingredient, in admixture with a pharmaceutically acceptablecarrier such as an organic or inorganic solid or liquid excipientsuitable for oral, parenteral, external including topical, enteral,intravenous, intramuscular, inhalant, nasal, intraarticular,intraspinal, transtracheal or transocular administration. Thepharmaceutical preparations may be solid, semi-solid or solutions suchas capsules, tablets, pellets, dragees, powders, granules,suppositories, ointments, creams, lotions, inhalants, injections,cataplasms, gels, tapes, eye drops, solution, syrups, aerosols,suspension, emulsion, or the like. If desired, there may be included inthese preparations, auxiliary substances, stabilizing agents, wetting oremulsifying agents, buffers and other commonly used additives.

While the dosage of the compound (I) will vary depending upon the ageand condition of a patient, an average single dose of about 0.1 mg, 1mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I)may be effective for treating Tachykinin-mediated diseases such asasthma and the like. In general, amounts between 0.1 mg/body and about1,000 mg/body may be administered per day.

In order to illustrate the usefulness of the object compound (I) and apharmaceutically acceptable salt thereof, the pharmacological test dataof some representative compounds of the present invention is shown inthe following.

All of the following Test Compounds showed more than 90% inhibition rateof ³ H-Substance P binding to guinea pig lung membranes at theconcentration of 1 μg/ml.

Test Compounds

The object compounds of the Examples 7-7, 17-1, 17-2, 17-4, 17-5, 17-10,17-11, 17-24, 19-1, 19-4, 19-10, 24-4 and 24-8

³ H-Substance P Binding to Guinea Pig Lung Membranes Test Method

³ H-Substance P Binding to Guinea Pig Lung Membranes

(a) Crude lung membrane preparation

Male Hartly strain guinea pigs were stunned and bled. The trachea andlung were removed and homogenized in ice-cold buffer (0.25M sucrose, 50mM Tris-HCl pH 7.5, 0.1 mM EDTA) by using Polytoron (Kinematica). Thehomogenate was centrifuged (1000×g, 10 minutes) to remove tissue clumpsand the supernatant was centrifuges (35000×g, 20 minutes) to yieldpellet. The pellet was resuspended in buffer (5 mM Tris-HCl pH 7.5),homogenized with a teflon homogenizer and centrifuged (35000×g, 20minutes) to yield pellet which was referred to as crude membranefractions. The obtained pellet was resuspended in buffer (50 mM Tris-HClpH 7.5) and stored at -70° C. until use.

(b) ³ H-Substance P binding to preparation membrane

Frozen crude membrane fractions were thawed and resuspended in Medium 1(50 mM Tris-HCl pH 7.5, 1 mM MnCl₂, 0.02% BSA, 2 μg/ml chymostatin, 4μg/ml leupeptin, 40 μg/ml bacitracin, 10 μM phosphoramidon). ³H-Substance P (1 nM) was incubated with 100 μl of the membranepreparations with or without test compounds in Medium 1 at 25° C. for 30minutes in a final volume of 500 μl. At the end of the incubationperiod, 5 ml ice-cold 50 mM Tris-HCl buffer was added to each tube andits content was quickly filtered over a Wahtman GF/B glass filter(pretreated with 0.1% polyethylene imine for 3 hours prior to use) underaspiration. Each of the filters was then washed four times with 5 ml ofice-cold buffer (50 mM Tris-HCl pH 7.5). The radioactivity was countedin 5 ml of Aquazol-2 in Packerd scintillation counter (Packerd TRI-CARB4530). All data presented are specific binding defined as thatdisplaceable by 5 μM unlabeled Substance P.

All of the following Test Compounds showed more than 90% inhibition rateof ¹²⁵ I-BH-Substance P binding to h-NK₁ receptors at the concentrationof 0.1 μg/ml.

Test Compounds

The object compounds of the Examples 17-50, 17-56, 17-57, 17-60, 19-13,21-3, 25-2, 26, 77, 79-4 and 79-6

¹²⁵ I-BH-Substance P Binding to h-NK₁ Receptors Test Method

¹²⁵ I-BH-Substance P Binding to h-NK₁ Receptors

(a) Crude CHO cell membrane preparation

CHO cells permanently expressing h-NK₁ receptors were harvested andhomogenized with a Dounce homogenizer at 4° C. in a buffer (0.25Msucrose, 25 mM Tris-HCl pH 7.4, 10 mM MgCl₂, 1 mM EDTA, 5 μg/mlp-APMSF). The homogenate was centrifuged (500×g, 10 minutes), and thepellet was resuspended in the same buffer, homogenized, and centrifuged.The two supernatants were combined and centrifuged (100,000×g, 1 hour).The crude cell membranes thus isolated were resuspended in buffer (25 mMTris-HCl pH 7.4, 10 mM MgCl₂, 1 mM EDTA, 5 μg/ml p-APMSF) and stored at-80° C. until use.

(b) ¹²⁵ I-BH-Substance P binding to preparation membrane Cell membranes(6 μg/ml) were incubated with ¹²⁵ I-BH-Substance P (0.1 nM) with orwithout test compounds in 0.25 ml of Medium 2(50 mM Tris-HCl pH 7.4, 5mM MnCl₂, 20 μg/ml chymostatin, 40 μg/ml bacitracin, 4 μg/ml leupeptin,5 μg/ml p-APMSF, 200 μg/ml BSA) at 22° C. for 90 minutes. At the end ofthe incubation period, the content was quickly filtered over a WahtmanGF/C glass filter (pretreated with 0.1% polyethylene imine for 3 hoursprior to use) under aspiration. Each of the filters was then washed fourtimes with 5 ml of buffer (50 mM Tris-HCl pH 7.4, 5 mM MnCl₂). Theradioactivity was counted by using Auto Gamma counter (Packerd RIASTAR5420A). All data presented are specific binding defined as thatdisplaceable by 3 μM unlabeled Substance P.

The following Preparations and Examples are given for the purpose ofillustrating this invention.

Preparation 1 ##STR20##

To a mixture of N² -(tert-butoxycarbonyl)-N¹ -formyl-D-tryptophan (3.99g) and N-benzyl glycin benzyl ester hydrochloride (3.50 g) indichloromethane (70 ml) was added triethylamine (5.85 ml) under nitrogenatmosphere. To the mixture was added 2-chloro-1-methylpyridinium iodide(3.67 g) at room temperature, and the resulting mixture was stirred for2 hours. After the reaction was completed, dichloromethane (30 ml) andwater (30 ml) were added. The organic layer was separated, washed with0.5N hydrochloric acid (10 ml), water (10 ml), aqueous sodiumbicarbonate solution (10 ml) and brine (20 ml) successively and driedover magnesium sulfate. After evaporation of the solvent, the residuewas purified on a silica gel column (140 g) eluting with a mixture oftoluene and ethyl acetate (4:1) to give (2R)-N-benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonylamino)-3-(N-formyl-1H-indol-3-yl)propanamide (6.41g) as an oil.

IR (CHCl₃): 3300, 2970, 1740, 1700, 1644, 1604 cm⁻¹

NMR (DMSO-d₆, δ): 0.89, 1.22 and 1.29 (9H, 3 s); 2.80-3.10 (2H, m);3.95-4.25 (2H, m); 4.40-4.90 (3H, m); 4.95-5.20 (2H, m); 7.05-7.75 (15H,m); 7.98 and 8.22 (1H, 2 br s); 9.22 and 9.61 (1H, 2 br s)

MASS: 570 (M+1)

Preparation 2

The following compounds were obtained according to a similar manner tothat of Preparation 1.

1)(2R)-N-Benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonylamino)-3-(3,4-dimethylphenyl)-propanamide

IR (Neat): 3300, 1740, 1700, 1645, 1500, 1360 cm⁻¹

NMR (CDCl₃, δ): 1.40 (9H, s); 2.2-2.3 (6H, m); 2.8-3.2 (2H, m); 3.7-4.2(2H, m); 4.5-5.0 (3H, m); 5.1-5.2 (2H, m); 5.2-5.3 (1H, m); 6.9-7.1 (5H,m); 7.2-7.5 (8H, m)

MASS: 531 (M+1), 475, 431

2) (2S)-N-Benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonylamino)-3-(N-formyl-1H-indol-3-yl)propanamide

IR (Neat): 3300, 1700, 1650, 1460 cm⁻¹

MASS: 570 (M+1), 514, 470

3)(2R)-N-Benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonylamino)-3-phenylpropanamide

IR (Neat): 3300, 1750-1630, 1150, 1013, 725 cm⁻¹

NMR (CDCl₃, δ): 1.38 and 1.62 (9H, 2 br s); 2.87-3.16 (2H, m); 3.74-4.73(5H, m); 4.94-5.28 (3H, m); 7.02-7.37 (15H, m)

4) (2R)-N-Benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonylamino)-3-(3,4-dichlorophenyl)-propanamide

mp: 171°-172° C.

IR (Nujol): 3250, 1730, 1680, 1645, 1520, 1360 cm⁻¹

NMR (DMSO-d₆, δ): 1.2-1.4 (9H, m); 2.7-3.0 (2H, m); 3.9-4.3 (2H, m);4.4-4.8 (3H, m); 5.12 (2H, s); 7.0-7.5 (14H, m)

MASS: 571 (M+1), 515, 471, 363

5)(2R)-N-Benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonylamino)-3-(benzob!thiophen-3-yl)propanamide

IR (Neat ): 3400, 3300, 1725, 1700, 1640, 1490, 1440, 1380, 1360 cm⁻¹

NMR (CDCl₃, δ): 1.1-1.4 (9H, m); 3.2-3.5 (2H, m); 3.6-4.8 (4H, m);4.8-5.4 (4H, m); 6.8-7.1 (2H, m); 7.1-7.4 (11H, m); 7.7-8.0 (2H, m)

MASS: 559 (M+1), 503, 459, 351

6)(2S)-N-Benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonylamino)-3-(3,4-dimethylphenyl)-propanamide

IR (Neat): 3300, 2960, 2920, 1742, 1700, 1646 cm⁻¹

NMR (CDCl₃, δ): 1.40 (9H, s); 2.18, 2.21 and 2.22 (6H, 3 s); 2.78-3.14(2H, m); 3.73-4.15 (2H, m); 4.44-5.35 (5H, m); 6.85-7.40 (14H, m)

MASS: 531 (M+1)

7) (2R,3R)-N-Benzyl-N-benzyloxycarbonylmethyl-2-(tert-butoxycarbonylamino)-3-(N-methyl-1H-indol-3-yl)-butanamide

IR (Neat): 3400, 3300, 1740, 1700, 1640, 1480, 1450, 1360 cm⁻¹

NMR (CDCl₃, δ): 1.3-1.5 (9H, m); 3.6-5.4 (15H, m); 7.0-7.8 (15H, m)

MASS: 570 (M+1), 538, 514, 471

Preparation 3 ##STR21##

To an ice-cooled solution of the object compound of Preparation 1 (6.39g) in dichloromethane (50 ml) was added 4N hydrogen chloride in dioxanesolution (50 ml). The mixture was stirred at the same temperature for 30minutes and at room temperature for 1 hour. After evaporation of thesolvent, the residue was partitioned between dichloromethane (50 ml) andaqueous sodium bicarbonate solution (30 ml). The organic layer wasseparated, dried over magnesium sulfate and filtered. To the filtratewas added triethylamine (1.67 ml) at room temperature, and the mixturewas stirred for 1.5 hours. After evaporation, the residue was trituratedwith diisopropyl ether, collected by filtration and dried to give(3R)-1-benzyl-3-(N-formyl-1H-indol-3-yl-methyl)piperazine-2,5-dione(3.93 g).

mp: 176°-178° C.

IR (Nujol): 3250, 1709, 1648, 1630 cm⁻¹

NMR (DMSO-d₆, δ): 2.95-3.30 and 3.35-3.70 (4H, 2 m); 4.22 (1H, d, J=14.6Hz); 4.30-4.40 (1H, m); 4.54 (1H, d, J=14.9 Hz); 6.80-7.75 (9H, m);7.95-8.50 (2H, m); 9.20 and 9.65 (1H, 2 br s)

MASS: 362 (M+1)

Preparation 4

The following compounds were obtained according to a similar manner tothat of Preparation 3.

1) (3R)-1-Benzyl-3-(3,4-dimethylbenzyl)piperazine-2,5-dione

mp: 191°-192° C. α!_(D) ²⁵ : -23.3° (C=1, DMF)

IR (Nujol): 3180, 1640, 1500, 1340 cm⁻¹

NMR (DMSO-d₆, δ) 2.11 and 2.16 (3H, 2 s); 2.82(1H, dd, J=4.8 and 13.5Hz); 3.13 (1H, dd, J=4.2 and 13.5 Hz); 2.76 (1H, d, J=17.1 Hz); 3.46(1H, d, J=17.1 Hz); 4.22 (1H, d, J=14.5 Hz); 4.55 (1H, d, J=14.5 Hz);4.2-4.3 (1H, m); 6.7-6.9 (3H, m); 7.0-7.1 (2H, m); 7.2-7.3 (3H, m); 8.31(1H, s)

MASS: 323 (M+1)

2) (3S)-1-Benzyl-3-(N-formyl-1H-indol-3-yl-methyl)-piperazine-2,5-dione

mp: 183°-184° C.

IR (Nujol): 3250, 1710, 1650 cm⁻¹

NMR (DMSO-d₆, δ): 3.0-4.6 (7H, m); 6.9-8.5 (10H, m); 8.4 (1H, s); 9.2(1H, s); 10.9 (1H, s)

MASS: 362 (M+1)

3) (3R)-1-Benzyl-3-benzylpiperazine-2,5-dione

mp: 180°-181° C.

IR (Nujol): 3240, 1675-1630, 1315, 1205, 1183, 1101, 1058, 740, 700 cm⁻¹

NMR (CDCl₃, δ): 2.92-3.56 (4H, m); 4.34-4.40 (1H, m); 4.48 (2H, s); 6.66(1H, s); 7.13-7.36 (10H, m)

4) (3R)-1-Benzyl-3-(3,4-dichlorobenzyl)piperazine-2,5-dione

mp: 167°-168° C.

α!_(D) ²⁵ : -12.8° (C=1.0, DMF)

IR (Nujol): 3250, 1670, 1645, 1440, 1320 cm⁻¹

NMR (DMSO-d₆, δ): 2.94 (1H, dd, J=4.8 and 13.4 Hz); 3.18 (1H, dd, J=4.8and 13.4 Hz); 3.19 (1H, d, J=17.4 Hz); 3.67 (1H, d, J=17.4 Hz); 4.19(1H, d, J=14.6 Hz); 4.3-4.4 (1H, m); 4.72 (1H, d, J=14.6 Hz); 7.0-7.2(3H, m); 7.3-7.4 (3H, m)); 7.4-7.5 (2H, m); 8.35-8.45 (1H, m)

MASS: 363 (M+1)

5) (3R)-1-Benzyl-3-(benzo b!thiophen-3-yl-methyl)-piperazine-2,5-dione

mp: 213°-215° C.

α!_(D) ²⁵ : +73.5° (C=1.0, DMF)

IR (Nujol): 3250, 1675, 1645, 1430, 1340, 1315 cm⁻¹

NMR (DMSO-d₆, δ): 2.94 (1H, d, J=17.3 Hz); 3.21 (1H, dd, J=4.5 and 14.5Hz); 3.43 (1H, dd, J=4.5 and 14.5 Hz); 3.46 (1H, d, J=17.3 Hz); 4.23(1H, d, J=14.5 Hz); 4.38 (1H, d, J=14.5 Hz); 4.3-4.4 (1H, m); 6.9-7.1(2H, m); 7.2-7.5 (6H, m); 7.8-8.1 (2H, m); 8.41 (1H, s)

MASS: 351 (M+1)

6) (3S)-1-Benzyl-3 -(3,4-dimethylbenzyl)piperazine-2,5-dione

mp: 188°-189° C.

α!_(D) ²¹ : +22.7° (C=1.0, DMF)

IR (Nujol): 3200, 1653 cm⁻¹

NMR (DMSO-d₆, δ): 2.11 (3H, s); 2.16 (3H, s);

2.77 (1H, d, J=17.0 Hz); 2.83 (1H, dd, J=13.5, 4.8 Hz); 3.07 (1H, dd,J=13.5, 4.2 Hz); 3.45 (1H, d, J=17.2 Hz); 4.22 (1H, m); 4.23 (1H, d,J=14.4 Hz); 4.55 (1H, d, J=14.6 Hz); 6.74-6.95 (3H, m); 7.04-7.38 (5H,m); 8.30 (1H, s)

MASS: 323 (M+1)

7) (3R)-1-Benzyl-3-(1R)-1-(N-methyl-1H-indol-3-yl)ethyl!piperazine-2,5-dione

mp: >240° C.

α!_(D) ²⁵ : +4.6° (C=1.0, DMF)

IR (Nujol): 3250, 1670, 1650, 1330, 1310 cm⁻¹

NMR (DMSO-d₆, δ): 1.39 (3H, d, J=7.4 Hz); 2.22 (1H, d, J=17.2 Hz); 3.09(1H, d, J=17.2 Hz); 3.67 (3H, s); 3.7-3.8 (1H, m); 3.78 (1H, d, J=14.8Hz); 4.0-4.1 (1H, m); 4.28 (1H, d, J=14.8 Hz); 6.7-6.9 (2H, m); 7.0-7.2(6H, m); 7.40 (1H, d, J=8.1 Hz); 7.52 (1H, d, J=7.9 Hz); 8.60 (1H, d,J=1.0 Hz)

MASS: 362 (M+1), 339

Preparation 5 ##STR22##

To an ice-cooled solution of the object compound of Preparation 3 (3.89g) in a mixture of methanol (175 ml) and tetrahydrofuran (50 ml) wasadded aqueous 0.1N sodium hydroxide solution (108 ml). The mixture wasstirred at the same temperature for 30 minutes and at room temperaturefor 1.5 hours. After evaporation of the solvent, the residue wasextracted with dichloromethane. The organic layer was washed with waterand an aqueous sodium chloride solution, and dried over magnesiumsulfate. Evaporation of the solvent gave(3R)-1-benzyl-3-(1H-indol-3-yl-methyl)piperazine-2,5-dione (3.68 g).

mp: 207°-208° C.

IR (Nujol): 3402, 1650 cm⁻¹

NMR (DMSO-d₆, δ): 2.68 (1H, d, J=17.2 Hz); 3.04 (1H, dd, J=14.4 and 4.4Hz); 3.20-3.40 (2H, m); 4.24 (1H, s); 4.10-4.40 (2H, m); 6.75-7.60 (10H,m); 8.35 (1H, s); 10.94 (1H, s)

MASS: 334 (M+1)

Preparation 6

The following compounds were obtained according to a similar manner tothat of Preparation 5.

1) (3S)-1-Benzyl-3-(1H-indol-3-yl-methyl)piperazine-2,5-dione

mp: 210°-211° C.

α!_(D) ²⁵ : +48.1° (C=1.0, DMF)

IR (Nujol): 3400, 3225, 1650, 1455 cm⁻¹

NMR (DMSO-d₆, δ): 3.0-3.4 (3H, m); 4.2 (4H, s); 6.8-7.6 (10H, m); 8.4(1H, s)

MASS: 334 (M+1)

2) (3R, 6R)-1-Benzyl-3-(1H-indol-3-yl-methyl)-6-methyl-piperazine-2,5-dione

α!_(D) ¹⁹ : +5.9° (C=1.0, MeOH)

IR (Neat): 3250, 1675, 1635, 1450, 1320 cm⁻¹

NMR (DMSO-d₆, δ): 0.35 (3H, d, J=7 Hz); 3.00-4.86 (6H, m); 6.95-8.32(11H, m); 10.94 (1H, s)

MASS: 348 (M+1)

3) (3R, 6S)-1-Benzyl-3-(1H-indol-3-yl-methyl)-6-piperazine-2,5-dione

IR (Neat): 3260, 1670, 1450, 1320 cm⁻¹

MASS: 348 (M+1)

Preparation 7 ##STR23##

To a suspension of lithium aluminum hydride (0.77 g) in tetrahydrofuran(40 ml) was added dropwise a solution of the object compound ofPreparation 5 (3.40 g) in tetrahydrofuran (40 ml) at 0° C. undernitrogen atmosphere. The mixture was stirred at room temperature for 50minutes and at refluxing temperature for 1 hour. The resulting mixturewas diluted with tetrahydrofuran (60 ml) and cooled to 0° C. Water (3.0ml) and aqueous 15% sodium hydroxide solution (0.8 ml) were addedslowly. The resulting insoluble inorganic material was removed byfiltration and washed with tetrahydrofuran. The filtrate and the washingwere combined and evaporated under reduced pressure to give(3R)-1-benzyl-3-(1H-indol-3-yl-methyl)piperazine (3.68 g) as an oil.

IR (CHCl₃): 3240, 3040, 2900 cm⁻¹

NMR (DMSO-d₆, δ): 1.70-2.00 and 2.30-2.45 (2H, 2 m); 2.50-3.00 (7H, m);3.25-3.60 (3H, m); 6.80-7.60 (10H, m); 10.80 (1H, s)

MASS: 306 (M+1)

Preparation 8

The following compounds were obtained according to a similar manner tothat of Preparation 7.

1) (3R)-1-Benzyl-3-(3,4-dimethylbenzyl) piperazine

IR (Neat): 3000-2750, 1670, 1500, 1450, 1360, 1320 cm⁻¹

NMR (CDCl₃, δ): 2.26 (6H, m); 1.8-3.0 (9H, m); 3.4-3.6 (2H, m); 6.9-7.1(3H, m); 7.2-7.5 (5H, m)

MASS: 295 (M+1)

2) (3R)-1,3-Dibenzylpiperazine

IR (Neat): 3020, 2850, 2800, 1600, 1493, 1453, 1322, 1134, 1027, 735,697 cm⁻¹

NMR (CDCl₃, δ): 1.68-2.15 (4H, m); 2.48-3.00 (6H, m); 3.43-3.58 (2H, m);7.18-7.33 (10H, m)

3) (3S)-1-Benzyl-3-(1H-indol-3-yl-methyl)piperazine

α!_(D) ²⁵ : +13.0° (C=1.0, DMF)

IR (Neat): 3400, 3150, 3025, 1450 cm⁻¹

NMR (DMSO-d₆, δ): 1.7-3.4 (9H, m); 6.9-7.5 (10H, m); 10.8 (1H, s)

MASS: 306 (M+1)

4) (3R)-1-Benzyl-3-(3,4-dichlorobenzyl)piperazine

IR (Neat): 3200 (br), 3100-2700, 1660, 1590, 1550, 1490, 1460, 1450,1400, 1320 cm⁻¹

NMR (CDCl₃, δ): 1.8-2.2 (3H, m); 2-4-3.0 (7H, m); 3.4-3.6 (2H, m); 7.02(1H, dd, J=2.0 and 8.2 Hz); 7.2-7.4 (7H, m)

MASS: 335 (M+1)

5) (3R)-1-Benzyl-3-(benzo b!thiophen-3-yl-methyl)-piperazine

IR (Neat): 2600-3100, 1660, 1490, 1450, 1425 cm⁻¹

NMR (CDCl₃, δ): 1.8-2.2 (4H, m) ; 2.7-3.3 (6H, m ); 3.4-3.6 (2H, m);7.1-7.5 (8H, m); 7.7-8.0 (2H, m)

MASS: 323 (M+1)

6) (3S)-1-Benzyl-3-(3,4-dimethylbenzyl)piperazine

IR (Neat): 3310-3250, 3020, 2930, 2800, 1668 cm⁻¹

NMR (CDCl₃, δ): 1.70 (1H, br s); 1.80-3.60 (11H, m); 2.23 (6H, s);6.83-7.40 (8H, m)

MASS: 295 (M+1)

7) (3R)-1-Benzyl-3- (1R)-1-(N-methyl-1H-indol-3-yl)-ethyl!piperazine

8) (3R,6R)-1-Benzyl-3-(1H-indol-3-yl-methyl)-6-methyl-piperazine

α!_(D) ¹⁹ : -21.2° (C=1.0, MeOH)

IR (Neat): 3400, 3200, 1650, 1450 cm⁻¹

NMR (DMSO-d₆, δ): 1.02 (3H, d, J=7 Hz); 2.25-4.10 (10H, m), 6.91-7.51(11H, m); 10.74 (1H, d, J=14 Hz)

MASS: 320 (M+1)

9) (3R, 6S)-1-Benzyl-3-(1H-indol-3-yl-methyl)-6-methyl-piperazine

α!_(D) ¹⁹ : +30.0° (C=1.0, MeOH)

IR (Neat): 3400, 3125, 1450, 1330 cm⁻¹

NMR (DMSO-d₆, δ): 1.02 (3H, d, J=7 Hz); 2.10-4.10 (10H, m); 6.91-7.47(10H, m); 10.76 (1H, s)

MASS: 320 (M+1)

10) (2S)-1-Benzyl-2-(2-naphthylmethyl)piperazine

α!_(D) ¹⁹ : +0.9° (C=1.0, CHCl₃)

IR (Neat): 2600-3100, 1650, 1600 cm⁻¹

NMR (CDCl₃, δ): 2.2-4.3 (10H, m); 3.48 (1H, d, J=13.5 Hz); 4.16 (1H, d,J=13.5 Hz); 7.0-7.9 (12H, m)

MASS: 317 (M+1)

11) (3S)-3-Benzyl-1-(3-phenylpropyl)piperazine

α!_(D) ²⁰ : +12.35° (C=1.075, MeOH)

IR (Neat): 3230, 3020, 2940, 2800 cm⁻¹

NMR (DMSO-d₆, δ): 1.50-1.95 (4H, m); 2.19 (2H, t, J=7.2 Hz); 2.55-3.45(10H, m); 7.00-7.20 (10H, m)

MASS: 295 (M+1)

Preparation 9

A solution of N-(tert-butoxycarbonyl)-D-alanine (3 g) indimethylformamide (5 ml) was added dropwise to a stirred solutionmixture of 60% sodium hydride (1.4 g) in dimethylformamide (5 ml) atice-bath temperature. After stirring for 30 minutes at the sametemperature, benzyl bromide (4.14 ml) was added and then the mixture wasstirred for 1 hour at the same temperature and then for 6 hours at roomtemperature. The reaction mixture was poured into a mixture of dilutehydrochloric acid and ice-water, and extracted with diisopropyl ether.The extract was washed with aqueous sodium bicarbonate solution andbrine successively and dried over magnesium sulfate. After evaporationof the solvent in vacuo, the residue was purified by columnchromatography on silica gel eluting with a mixture of n-hexane andethyl acetate (2:1) to give an oily product, which was dissolved indichloromethane (40 ml). To the solution was added 4N hydrogen chloridein dioxane solution (7 ml) at ice-bath temperature. The resultingmixture was stirred for 1.5 hours at room temperature and thenconcentrated under reduced pressure to give benzyl(2R)-2-(N-benzylamino)propionate hydrochloride (2.2 g).

α!_(D) ¹⁹ : +6.6° (C=1.0, MeOH)

IR (Nujol): 2700, 2600, 2500, 2375, 1740, 1460 cm⁻¹

NMR (DMSO-d₆, δ): 1.55 (3H, d, J=7 Hz); 4.1-4.28 (3H, m); 5.25 (2H, s);7.4-7.56 (10H, m); 9.8 (1H, br s); 10.25 (1H, br s)

MASS: 270 (M+1) (free)

Preparation 10

The following compound was obtained according to a similar manner tothat of Preparation 9.

Benzyl (2S)-(N-benzylamino)propionate hydrochloride

IR (Neat): 3300, 1730, 1450, 1175, 1150 cm⁻¹

NMR (CDCl₃, δ): 1.33 (3H, d, J=7 Hz); 3.43 (1H, q, J=7 Hz); 3.72 (2H, q,J=14 Hz); 5.17 (2H, s); 7.2-7.36 (10H, m)

MASS: 270 (M+1) (free)

Preparation 11

1) N,N-Diisopropylethylamine (8.26 ml) was added to a stirred mixture ofN-(tert-butoxycarbonyl)-L-naphthylalanine (10.0 g) and benzyl bromide(4.52 ml) in dimethylformamide (100 ml) at 5° C. The mixture was stirredfor 4.5 hours at room temperature and then poured into ice-water (500ml). The desired product was extracted with ethyl ether and the extractwas washed successively with dilute hydrochloric acid, aqueous sodiumbicarbonate solution and brine, and dried over magnesium sulfate. Afterevaporation of the solvent, the residue was triturated with diisopropylether to give benzyl (2S)-2- N-(tert-butoxycarbonyl) amino!-3-(2-naphthyl)propionate (13.4 g).

mp: 90°-91° C.

IR (Nujol) 3380, 1735, 1690, 1520, 1320 cm⁻¹

2) A solution of benzyl (2S)-2-N-(tert-butoxycarbonyl)amino!-3-(2-naphthyl)propionate (5.0 g) indimethylformamide (50 ml) was added dropwise to a stirred mixture of 60%sodium hydride (0.6 g) and dimethylformamide (50 ml) at ice-bathtemperature. After the addition was completed, the reaction mixture wasstirred at the same temperature for 30 minutes. Benzyl bromide (1.76 ml)was added and then the whole mixture was stirred for 3.5 hours.Additional benzyl bromide (0.4 ml) was added and then stirred for 2.5hours. The reaction mixture was poured into ice-water and extracted withethyl acetate. The extract was washed successively with 1N hydrochloricacid, aqueous sodium bicarbonate solution and brine and dried overmagnesium sulfate. After evaporation of the solvent in vacuo, theresidue was purified by column chromatography on silica gel eluting witha mixture of n-hexane and ethyl acetate (4:1) to give benzyl (2S)-2-N-(tert-butoxycarbonyl)-N-benzylamino!-3-(2-naphthyl)propionate (3.53g).

IR (Neat): 3100-2800, 1740, 1690, 1600 cm⁻¹

NMR (CDCl₃, δ): 1.1-1.5 (9H, m); 3.2-4.6 (5H, m); 4.9-5.1 (2H, m);6.9-7.9 (17H, m)

Preparation 12

To a mixture of N² -(tert-butoxycarbonyl)-N¹ -formyl-D-tryptophan (2.17g) and benzyl (2R)-2-(N-benzylamino)propionate hydrochloride (2.0 g) indichloromethane (30 ml) was added triethylamine (2.3 ml) under nitrogenatmosphere. To the mixture was added 2-chloro-1-methylpyridinium iodide(1.84 g) at room temperature, and the resulting mixture was stirred for2 hours and left overnight. The reaction mixture was washed successivelywith dilute hydrochloric acid, aqueous sodium bicarbonate solution andbrine, and dried over magnesium sulfate. After evaporation of thesolvent, the residue was dissolved in dichloromethane (30 ml). Asolution of 4N hydrogen chloride in dioxane solution (10 ml) was addedthereto at ice-bath temperature and-then the resulting mixture wasstirred for 1 hour at room temperature. The reaction mixture wasconcentrated under reduced pressure. The residue was partitioned betweendichloromethane and aqueous saturated sodium bicarbonate solution. Theorganic layer was separated, washed with brine, dried over magnesiumsulfate and filtered. To the filtrate was added triethylamine (1 ml) andthe resulting mixture was stirred for 1 hour at room temperature. Thereaction mixture was concentrated under reduced pressure. The residuewas purified on a silica gel column (60 g) eluting with a mixture ofn-hexane and ethyl acetate (2:1) to give(3R,6R)-1-benzyl-3-(N-formyl-1H-indol-3-yl-methyl)-6-methylpiperazine-2,5-dione(1.3 g).

IR (Neat): 3200, 1700, 1675, 1650, 1460 cm⁻¹

NMR (DMSO-d₆, δ): 0.64 (3H, d, J=7 Hz); 3.09-4.83 (6H, m); 7.1-8.4 (10H,m)

MASS: 376 (M+1)

Preparation 13

The following compound was obtained according to a similar manner tothat of Preparation 12.

(3R,6S)-1-Benzyl-3-(N-formyl-1H-indol-3-yl-methyl)-6-methylpiperazine-2,5-dione

IR (Neat): 3200, 1675, 1450, 1370, 1320 cm⁻¹

NMR (DMSO-d₆, δ): 1.26 (3H, d, J=7 Hz); 3.08-3.44 (3H, m); 3.94-4.04(1H, m); 4.52-4.64 (1H, m); 4.97-5.10 (1H, m); 6.83-7.81 (10H, m); 8.37(1H, s)

MASS: 376 (M+1)

Preparation 14

Benzyl (2S)-2-N-(tert-butoxycarbonyl)-N-benzylamino!-3-(2-naphthyl)propionate (10.5 g)was dissolved in methanol (100 ml) and aqueous 1N sodium hydroxidesolution (20 ml) was added at ice-bath temperature. The mixture wasstirred at room temperature overnight. The reaction mixture was pouredinto ice-water and extracted with diisopropyl ether. The aqueous layerwas adjusted to pH 3 by adding dilute hydrochloric acid and extractedwith ethyl acetate. The extract was washed with brine and dried overmagnesium sulfate. Evaporation of the solvent gaveN-benzyl-N-(tert-butoxycarbonyl)-3-(2-naphthyl)-L-alanine (3.0 g).

NMR (CDCl₃, δ): 1.4-1.6 (9H, m); 3.2-4.6 (5H, m); 5.6-6.4 (1H, br s);6.7-7.8 (12H, m)

MASS: 404 (M-1)

Preparation 15

To a stirred mixture ofN-benzyl-N-(tert-butoxycarbonyl)-3-(2-naphthyl)-L-alanine (2.9 g),glycine methyl ester hydrochloride (0.9 g) and 1-hydroxybenzotriazolehydrate (1.06 g) in dichloromethane (50 ml) was added dropwise1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.43 ml) at ice-bathtemperature. The resulting mixture was stirred at room temperature for 2days and then evaporated under reduced pressure. The residue waspartitioned between ethyl acetate and aqueous sodium bicarbonatesolution. The organic layer was separated, washed with dilutehydrochloric acid and brine, and dried over magnesium sulfate.Evaporation of the solvent gave (2S)-2-N-benzyl-N-(tert-butoxycarbonyl)amino!-N-methoxycarbonylmethyl-3-(2-naphthyl)propanamide.

IR (Neat): 3350, 3100-2800, 1750, 1680, 1660, 1600, 1530 cm⁻¹

NMR (CDCl₃, δ): 1.3-1.5 (9H, m); 3.2-4.7 (8H, m); 3.69 (3H, s); 6.8-7.9(12H, m)

MASS: 477 (M+1), 421, 337

Preparation 16

To a stirred solution of the object compound of Preparation 15 (3.1 g)in dichloromethane (30 ml) was added dropwise 4N hydrogen chloride indioxane solution (30 ml) at ice-bath temperature. The resulting mixturewas stirred at room temperature for 1 hour and then evaporated underreduced pressure to give an oil, which was partitioned between ethylacetate and aqueous sodium bicarbonate solution. The ethyl acetate layerwas washed with brine and dried over magnesium sulfate. Evaporation ofthe solvent in vacuo gave a syrup, which was dissolved in a mixture ofacetic acid (25 ml) and toluene (25 ml). The resulting mixture washeated at reflux temperature for 3 hours and concentrated under reducedpressure. The residue was triturated with a mixed solvent of water anddiisopropyl ether to afford(2S)-1-benzyl-2-(2-naphthylmethyl)piperazine-3,6-dione (1.6 g).

mp 160°-161° C.

α!_(D) ¹⁹ : +0.7° (C=1.0, MeOH)

IR (Nujol): 3250, 1670, 1650, 1430, 1350 cm⁻¹

NMR (DMSO-d₆, δ): 2.5-2.6 (2H, m); 3.1-3.5 (2H, m); 4.03 (1H, t, J=4.8Hz); 4.11 (1H, d, J=15.1); 5.16 (1H, d, J=15.1 Hz); 7.2-8.0 (12H, m);8.09 (1H, br s)

MASS: 345 (M+1)

Preparation 17

A solution of di-tert-butyl dicarbonate (218 mg) in acetone (2 ml) wasadded dropwise to a stirred mixture of(3R)-1-benzyl-3-(1H-indol-3-yl-methyl)piperazine (305 mg) andtriethylamine (150 mg) in a mixed solvent of acetone (3 ml) and water (3ml) at ice-bath temperature. The resulting mixture was stirred at roomtemperature for 1 hour and evaporated under reduced pressure. Theresidue was partitioned between ethyl acetate and water. The organiclayer was separated, washed successively with dilute hydrochloric acid,aqueous sodium bicarbonate solution and brine, and dried over magnesiumsulfate. After evaporation of the solvent in vacuo, the residue wasdissolved in ethanol (10 ml) and then treated with ammonium formate (315mg) in the presence of 10% Pd charcoal at 90° C. under nitrogenatmosphere. After stirring for 30 minutes, the reaction mixture wasfiltered and concentrated under reduced pressure to give(2R)-1-(tert-butoxycarbonyl)-2-(1H-indol-3-yl-methyl)piperazine (310mg).

IR (Neat): 3300, 1660, 1410 cm⁻¹

NMR (DMSO-d₆, δ) 1.1 (9H, s); 2.4-4.4 (9H, m); 6.9-7.6 (5H, m); 10.8(1H, s)

MASS: 316 (M+1)

Preparation 18

To a stirred mixture of(2R)-1-(tert-butoxycarbonyl)-2-(1H-indol-3-yl-methyl)piperazine (250 mg)and potassium carbonate (165 mg) in dimethylformamide (1 ml) was addedtrans-cinnamoyl chloride (150 mg) at room temperature. The resultingmixture was stirred for 3 hours and then poured into water. Extractionwith ethyl acetate followed by drying over magnesium sulfate andevaporation in vacuo gave a syrup, which was dissolved indichloromethane (2 ml). A solution of 4N hydrogen chloride in dioxanesolution (1 ml) was added to the solution at ice-bath temperature andthe resulting mixture was stirred for 1 hour at room temperature. Thereaction mixture was concentrated under reduced pressure. The residuewas partitioned between ethyl acetate and aqueous saturated sodiumbicarbonate solution. The organic layer was separated, washed with brineand dried over magnesium sulfate. Evaporation of the solvent in vacuogave (3R)-1-(transcinnamoyl)-3-(1H-indol-3-yl-methyl)piperazine (166mg).

α!_(D) ²⁶ : -37.5° (C=1.0, MeOH)

IR (Neat) 3250, 1640, 1590, 1435 cm⁻¹

NMR (DMSO-d₆, δ): 2.3-4.4 (9H, m); 6.9-7.7 (13H, m); 10.9 (1H, s)

MASS: 346 (M+1) (to be continued on the next page)

EXAMPLE 1 ##STR24##

To a mixture of 3,5-bis(trifluoromethyl)benzoic acid (1.15 g) and(3R)-1-benzyl-3-(1H-indol-3-yl-methyl)piperazine (1.61 g) indichloromethane (80 ml) was added triethylamine (1.55 ml) at roomtemperature under nitrogen atmosphere. 2-Chloro-1-methylpyridiniumiodide (1.37 g) was added, and the mixture was stirred at roomtemperature for 2.5 hours. The resulting mixture was poured into water(20 ml). The organic layer was washed successively with 0.5Nhydrochloric acid, water, aqueous sodium bicarbonate solution and brine,and dried over magnesium sulfate. After evaporation under reducedpressure, the residue was chromatographed on silica gel withtoluene--ethyl acetate (4:1) as an eluent to give (2R)-4-benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine(0.87 g) as a syrup.

IR (CHCl₃): 3430, 3300, 3000, 2910, 2800, 1630-1610 cm⁻¹

NMR (DMSO-d₆, δ): 1.90-2.40 (2H, m); 2.70-3.90 (8H, m); 4.25-4.40 and4.75-4.90 (1H, m); 6.50-7.45 (10H, m); 7.50-8.25 (3H, m); 10.77 (1H, s)

MASS: 546 (M+1)

Example 2

The following compounds were obtained according to a similar manner tothat of Example 1.

1) (2R)-4-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)piperazine

IR (Neat): 3000-2700, 1640, 1500, 1430, 1350 cm⁻¹

NMR (CDCl₃, δ): 2.1-2.3 (6H, m); 2.1-2.2 (2H, m); 2.6-3.7 (8H, m);4.5-5.1 (1H, m); 6.5-6.7 (2H, m); 6.9-7.6 (7H, m); 7.8-7.9 (2H, m)

MASS: 535 (M+1)

2)(2R)-4-Benzyl-1-(3,5-dimethylbenzoyl)-2-(1H-indol-3-yl-methyl)piperazine

IR (Nujol): 3200, 1600 cm⁻¹

NMR (DMSO-d₆, δ) 1.95-4.40 (9H, m); 2.17 (6H, s); 6.6-7.7 (13H, m);10.74 (1H, s)

MASS: 438 (M+1)

Example 3 ##STR25##

To an ice-cooled mixture of(3R)-1-benzyl-3-(1H-indol-3-yl-methyl)piperazine (305 mg) and potassiumcarbonate (207 mg) in dimethylformamide (1 ml) was added3,5-dichlorobenzoyl chloride (210 mg). The mixture was stirred at roomtemperature for 1 hour. Ethyl acetate and water were added. The organiclayer was washed successively with aqueous sodium bicarbonate solutionand brine and dried over magnesium sulfate. After evaporation of thesolvent, the residue was dissolved in ethyl ether. After insolublematerial was removed by filtration, the filtrate was concentrated underreduced pressure and the residue was triturated with diisopropyl ether,collected by filtration and dried to give(2R)-4-benzyl-1-(3,5-dichlorobenzoyl)-2-(1H-indol-3-yl-methyl)piperazine.

mp: 93°-98° C.

IR (Nujol): 3225, 1600 cm⁻¹

NMR (DMSO-d₆, δ): 1.9-4.8 (9H, m); 6.7-7.8 (13H, m); 10.79 (1H, s)

MASS: 478 (M+1)

Example 4

The following compounds were obtained according to a similar manner tothat of Example 3.

1) (2R)-4-Benzyl-1-benzoyl-2-(1H-indol-3-yl-methyl)-piperazine

mp: 165°-167° C.

IR (Nujol): 3200, 1600, 1440, 1425 cm⁻¹

NMR (DMSO-d₆, δ): 1.9-4.8 (9H, m); 6.5-7.7 (15H, m); 10.7 (1H, s)

MASS: 410 (M+1)

2) (2R)-4-Benzyl-1-benzenesulfonyl-2-(1H-indol-3-yl-methyl)piperazine

mp: 120°-123° C.

IR (Nujol): 3560, 3450, 3225, 1310, 1160 cm⁻¹

NMR (DMSO-d₆, δ): 1.6-1.9 (2H, m); 2.5-2.8 (2H, m); 3.16-4.03 (5H, m);6.72-7.83 (15H, m); 10.76 (1H, s)

MASS: 446 (M+1)

3) (2R)-2,4-Dibenzyl-1- 3,5-bis(trifluoromethyl)-benzoyl!piperazine

α!_(D) ²⁸ : -13.0° (C=1.0, MeOH)

IR (Neat): 3020, 2930, 2800, 1635, 1430, 1270, 1125, 900, 740 cm⁻¹

NMR (DMSO-d₆, δ): 1.99-2.30 (2H, m); 2.60-3.70 (8H, m); 4.30-4.90 (1H,m); 6.80-8.17 (13H, m)

MASS: 507 (M+1)

4) (2S)-4-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

IR (Neat): 3275, 1625, 1430 cm⁻¹

NMR (DMSO-d₆, δ): 1.9-4.8 (11H, m); 6.6-8.4 (13H, m); 10.8 (1H, m)

MASS: 546 (M+1)

5) (2R)-4-Benzyl-1-2,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

mp 186°-187° C.

IR (Nujol): 3200, 1625, 1330, 1310 cm⁻¹

NMR (DMSO-d₆, δ): 1.8-4.9 (11H, m); 6.6-8.2 (13H, m); 10.7-10.9 (1H, m)

MASS: 546 (M+1)

6) (2R)-4-Benzyl-1-2,4-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

IR (Neat) 3250, 1620, 1340 cm⁻¹

NMR (DMSO-d₆, δ) 2.6-4.9 (11H, m); 6.6-8.3 (13H, m); 10.8-10.9 (1H, m)

MASS: 546 (M+1)

7) (2R)-4-Benzyl-1-(3-phenoxybenzoyl)-2-(1H-indol-3-yl-methyl)piperazine

mp: 165°-167° C.

IR (Nujol) 3200, 1600, 1450 cm⁻¹

NMR (DMSO-d₆, δ): 1.9-4.8 (11H, m); 6.7-7.8 (19H, m); 10.7 (1H, s)

MASS: 502 (M+1)

8) (2R)-4-Benzyl-1-2,6-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

IR (Neat): 3300, 1640, 1590, 1430 cm⁻¹

NMR (DMSO-d₆, δ) 1.7-3.6 (11H, m); 6.8-8.4 (13H, m); 10.8 (1H, s)

MASS: 546 (M+1)

Example 5 ##STR26##

To an ice-cooled solution of (2R)-4-benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine(1.15 g) in dimethylformamide (60 ml) was added 60% sodium hydride (0.1g) under nitrogen atmosphere, and the mixture was stirred for 5 minutes.After addition of methyl iodide (0.13 ml), the reaction mixture wasstirred for 40 minutes. The reaction was quenched with 0.5N hydrochloricacid (60 ml) and diluted with dichloromethane (80 ml). The organic layerwas washed with water, aqueous sodium bicarbonate solution and brine,and dried over magnesium sulfate. After removal of the solvent, theresidue was purified on a silica gel column eluting with a mixture oftoluene and ethyl acetate (10:1) to give (2R)-4-benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-2-(N-methyl-1H-indol-3-yl-methyl)piperazine(1.12 g) as a syrup.

IR (CHCl₃): 3010, 2930, 2800, 2760, 1635 cm⁻¹

NMR (DMSO-d₆, δ): 1.88-2.35 (2H, m); 2.59-3.15 (4H, m); 3.15-3.48 (2H,m); 3.58 and 3.64 (3H, 2 s); 3.48-3.80 (2H, m); 4.28-4.44 and 4.67-4.85(1H, 2 m); 6.50-7.48 (10H, m); 7.20, 7.99, 8.06 and 8.20 (3H, 4 m)

MASS: 560 (M+1)

Example 6 ##STR27##

A mixture of (2R)-4-benzyl-1-3,5-bis(trifluoro-methyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine(5.20 g), ammonium formate (1.50 g) and 10% Pd charcoal (0.52 g) inethanol (50 ml) was refluxed for 7.5 hours under nitrogen atmosphere.The reaction mixture was cooled to room temperature and filtered throughCelite pad. The filtrate was concentrated under reduced pressure and theresidue was purified on a silica gel column eluting with a mixture ofdichloromethane and methanol (20:1) to give (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine(2.67 g, 61.5%) as a syrup.

IR (CHCl₃): 3280, 2900, 1622 cm⁻¹

NMR (DMSO-d₆, δ): 2.50-3.50 (9H, m); 3.6-4.8 (1H, m); 6.55-7.40 (5H, m);7.50-8.22 (3H, m); 10.84 (1H, s)

MASS: 456 (M+1)

Example 7

The following compounds were obtained according to a similar manner tothat of Example 6.

1) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)piperazine

IR (Neat): 3320, 3050-2750, 1630, 1500, 1430, 1350, 1320 cm⁻¹

NMR (CDCl₃, δ) 2.24 (6H, s); 2.2-2.3 (2H, m); 2.6-3.8 (9H, m); 4.4-5.2(1H, m); 6.6-7.9 (6H, m)

MASS: 445 (M+1)

2) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(N-methyl-1H-indol-3-yl-methyl)piperazine

IR (CHCl₃): 3320, 2940, 2830, 1628 cm⁻¹

NMR (DMSO-d₆, δ): 2.50-3.59 (9H, m); 3.69, 3.70 (3H, s); 4.15-4.35,4.65-4.84 (1H, m); 6.64-8.22 (8H, m)

MASS: 470 (M+1)

3) (2R)-1-Benzoyl-2-(1H-indol-3-yl-methyl)piperazine

mp: 211°-213° C.

α!_(D) ²⁵ : +51.4° (C=1.0, MeOH)

IR (Nujol): 3200, 1600, 1590 cm⁻¹

NMR (DMSO-d₆, δ) 2.5-4.7 (9H, m); 6.6-7.9 (10H, m); 10.8 (1H, s)

MASS: 320 (M+1)

4) (2R)-1-Benzenesulfonyl-2-(1H-indol-3-yl-methyl)-piperazine

mp: 152-154° c

α!_(D) ²⁵ : -1.70 (C=1.0, MeOH)

IR (Nujol): 3350, 1290, 1150 cm⁻¹

NMR (DMSO-d₆, δ): 2.25-3.60 (8H, m); 3.95-4.0 (1H, m); 6.96-7.84 (10H,m); 10.86 (1H, s)

MASS: 355 (M+1)

5) (2R)-1-(3,5-Dimethylbenzoyl)-2-(1H-indol-3-yl-methyl)piperazine

α!_(D) ²⁵ : +44.4° (C=1.0, MeOH)

IR (Neat): 3225, 1600, 1430, 1330 cm⁻¹

NMR (DMSO-d₆, δ): 2.18 (6H, s); 2.5-4.8 (9H, m); 6.55-7.34 (8H, m);10.85 (1H, s)

MASS: 348 (M+1)

6) (2R)-1-(3,5-Dichlorobenzoyl)-2-(1H-indol-3-yl-methyl)piperazine

α!_(D) ²⁵ : +34.7° (C=1.0, MeOH)

IR (Nujol): 3200, 1620, 1610 cm⁻¹

NMR (DMSO-d₆, δ) 2.9-4.5 (9H, m); 6.7-7.5 (9H, m); 10.96 (1H, s)

MASS: 388 (M+1), 354, 320

7) (2R)-2-Benzoyl-1- 3,5-bis(trifluoromethyl)benzoyl!-piperazine

α!_(D) ²⁸ : -17.6° (C=1.0, MeOH)

IR (Neat): 3320, 2750, 1620, 1430, 1270, 1120, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.50-3.50 (9H, m); 4.19-4.90 (1H, m); 6.80-7.00 (1H,m); 7.15-7.40 (5H, m); 7.63 (1H, s); 8.10 (1H, m)

MASS: 417 (M+1)

8) (2S)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

IR (Neat): 3250, 1625, 1430 cm⁻¹

NMR (DMSO-d₆, δ): 2.6-4.9 (9H, m); 6.6-8.2 (8H, m); 8.4 (1H, s); 10.9(1H, s)

MASS: 456 (M+1)

Example 8 ##STR28##

To a stirred mixture of (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)piperazine (0.1g) and triethylamine (0.125 ml) in dimethylformamide (0.6 ml) was addedethyl 2-methoxybenzenecarboximidate hydro-chloride (62 mg) at roomtemperature. The resulting mixture was heated at 100° C. for 1 hour. Themixture was poured into ice-water, and extracted by ethyl acetate. Theextract was purified on a silica gel column (dichloromethane/methanol)and treatment with 4N hydrogen chloride in ethyl acetate solution gave(2R)-1- 3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-1-imino-2-(2-methoxyphenyl)ethyl!piperazine hydrochloride.

mp: 237°-238° C.

α!_(D) ²⁵ : -16.2° (C=0.88, MeOH)

IR (Nujol): 3400-3200, 1680, 1620, 1490, 1330, 1270 cm⁻¹

NMR (DMSO-d₆, δ): 2.1-2.2 (6H, m); 2.6-4.5 (14H, m); 6.4-6.6 (1H, m);6.9-7.5 (8H, m); 8.1-8.2 (1H, m); 9.3-9.6 (1H, m); 9.8-9.1 (1H, m)

MASS: 592 (M+1) (free), 445

Example 9 ##STR29##

(2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(methoxycarbonylmethyl)piperazine(0.2 g) was treated with 20% ammonia methanol solution (5 ml), and theresulting mixture was left overnight in a refrigerator. The reactionmixture was concentrated under reduced pressure and the residue waspurified on a silica gel column (7 g) eluting with a mixture ofdichloromethane and methanol (10:1) to give (2R)-2-benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(carbamoylmethyl)-piperazine. Thiscompound was treated with 4N hydrogen chloride in ethyl acetate solutionto give the corresponding hydrochloride (0.18 g) as a white powder.

mp: 166°-169° C.

α!_(D) ²⁶ : -6.4° (C=1.0, MeOH)

IR (Nujol): 3600-3050, 2700-2000, 1685, 1635, 1275, 1128, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.70-5.15 (13H, m); 6.90-7.00 (1H, m); 7.10-7.50 (5H,m); 7.65-7.85 (1H, m); 8.10-8.25 (1H, m)

MASS: 474 (M+1) (free), 417

Example 10 ##STR30##

To a solution of (2R)-2-benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(methoxycarbonylmethyl)-piperazine(0.18 g) in methanol (18 ml) was added aqueous 1N sodium hydroxidesolution (4.3 ml), and the mixture was stirred at room temperature for50 minutes. The reaction mixture was evaporated under reduced pressureand the residue was diluted with water (4 ml). IN Hydrochloric acid (4.3ml) was added to the solution at 0° C. and the resulting precipitate wascollected by filtration and washed with water. The obtained carboxylicacid was converted to the corresponding hydrochloride by treatment with4N hydrogen chloride in ethyl acetate solution to give (2R)-2-benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(carboxymethyl)piperazinehydrochloride (0.12 g).

mp: 158°-161° C.

α!_(d) ²⁵ : -11.5° (C=1.0, MeOH)

IR (Nujol): 3650-3100, 2700-2100, 1730, 1630, 1276, 1130, 903 cm⁻¹

NMR (DMSO-d₆, δ): 2.70-5.15 (11H, m); 6.90-8.25 (8H, m)

MASS: 475 (M+1) (free), 417

Example 11 ##STR31##

A mixture of (2R)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)piperazine(0.17 g), 1-bromo-3-phenylpropane (0.08 g) and potassium carbonate (0.15g) in dry dimethylformamide (10 ml) was stirred at room temperatureunder nitrogen atmosphere. After 2 hours, additional1-bromo-3-phenylpropane (0.14 ml) and potassium carbonate (0.15 g) wereadded, and the mixture was stirred overnight. Water (50 ml) anddichloromethane (50 ml) were added to the mixture. The dichloromethanelayer was washed with brine and dried over magnesium sulfate. Afterevaporation of the solvent, the residue was purified on a silica gelcolumn (10 g) eluting with a mixture of toluene and ethyl acetate (4:1)to give (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(3-phenylpropyl)piperazine(0.17 g) as a syrup.

IR (CHCl₃): 3300, 2930, 1686, 1630 cm⁻¹

NMR (DMSO-d₆, δ): 1.62-2.44 (6H, m); 2.67 (2H, t); 2.80-3.30 (5H, m);3.75-4.40, 4.80-4.95 (2H, m); 6.53-7.35 (10H, m); 7.40-8.20 (3H, m);10.85 (1H, s)

MASS: 574 (M+1)

Example 12

The following compounds were obtained according to a similar manner tothat of Example 11.

1) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl)-2-(3,4-dimethylbenzyl)-4-(3-phenylpropyl)piperazine

IR (Neat): 3000-2750 (bra), 1630, 1500, 1440, 1350 cm⁻¹

NMR (CDCl₃, δ): 1.82 (2H, sext, J=7.4 Hz); 2.35 (2H, t, J=7.4 Hz); 2.71(2H, t, J=7.4 Hz); 2.1-2.2 (6H, m); 2.1-2.5 (2H, m); 2.7-3.7 (6H, m);4.5-5.2 (1H, m); 6.6-7.5 (10H, m); 7.28 (1H, s)

MASS: 563 (M+1)

2) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(trans-cinnamyl)piperazinehydrochloride

mp: 187°-190° C.

α!_(D) ²⁷ : +0.4° (C=1.0, MeOH)

IR (Nujol): 3700-3100, 2700-2000, 1650, 1278, 1185, 1120, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.85-5.20 (13H, m); 6.45-6.65 (1H, m); 6.80-7.05 (2H,m); 7.15-8.30 (10H, m)

MASS: 533 (M+1) (free)

3) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(5-phenylpentyl)piperazinehydrochloride

mp: 80°-88° C.

α!_(D) ²⁶ : +0.4° (C=1.0, MeOH)

IR (Nujol): 3350, 2700-2100, 1635, 1275, 1170, 1125, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.30-1.40 (2H, m); 1.50-1.90 (4H, m); 2.50-2.70 (2H,m); 2.80-4.10 (10H, m); 4.50-5.20 (1H, m); 6.90-7.00 (1H, m); 7.10-7.50(10H, m); 7.70 (1H, s); 8.17-8.22 (1H, m); 10.80-11.20 (2H, m)

MASS: 563 (M+1) (free)

4) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(4-phenylbutyl)piperazinehydrochloride

mp: 88°-91° C.

α!_(D) ²⁶ : +2.9° (C=1.0, MeOH)

IR (Nujol): 3600-3100, 2700-2000, 1635, 1275, 1170, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.50-1.90 (4H, m); 2.50-2.70 (2H, m); 2.70-4.10 (10H,m); 4.70-5.20 (1H, m); 6.90-7.00 (1H, m); 7.20-7.50 (10H, m); 7.72 (1H,s); 8.15-8.22 (1H, m); 10.90-11.25 (1H, m)

MASS: 549 (M+1) (free)

5) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-methylpiperazinehydrochloride

α!_(D) ²⁶ : -2.6° (C=1.0, MeOH)

IR (Nujol): 3370, 2750-2100, 1635, 1278, 1178, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.82 (3H, s); 2.80-4.10 (8H, m); 4.50-5.20 (1H, m);6.95-6.98 (1H, m); 7.20-7.60 (5H, m); 7.66 (1H, s); 8.17-8.22 (1H, m);11.00-11.40 (1H, m)

MASS: 431 (M+1) (free)

6) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-ethylpiperazinehydrochloride

mp: >220° C.

α!_(D) ²⁶ : -1.2° (C=1.0, MeOH)

IR (Nujol): 3400, 2600, 1615, 1273, 1185, 1140, 904 cm⁻¹

NMR (DMSO-d₆, δ): 1.34 (3H, t, J=7.4 Hz); 2.80-4.15 (11H, m); 4.50-5.20(1H, m); 6.90-7.00 (1H, m); 7.20-7.45 (5H, m); 7.72 (1H, s); 8.17-8.23(1H, m); 10.90-11.40 (1H, m)

MASS: 445 (M+1) (free)

7) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-isopropylpiperazine hydrochloride

mp: 218°-221° C.

α!_(D) ²⁶ : +1.1° (C=1.0, MeOH)

IR (Nujol): 3530, 3390, 2700-2300, 1640, 1272, 1134, 904 cm⁻¹

NMR (DMSO-d₆, δ): 1.26-1.40 (6H, m); 2.80-4.10 (9H, m); 4.50-5.20 (1H,m); 6.90-7.00 (1H, m); 7.20-7.60 (5H, m); 7.81 (1H, m); 8.17-8.23 (1H,m)

MASS: 459 (M+1) (free)

8) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(diphenylmethyl)piperazinehydrochloride

mp: 118°-120° C.

α!_(D) ²⁶ : +40.3° (C=1.0, MeOH)

IR (Nujol): 3500-3100, 2700-2100, 1640, 1277, 1175, 1133, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.69 (10H, m); 6.90-8.30 (18H, m); 12.10 (1H, brs)

MASS: 583 (M+1) (free), 417, 167

9) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-2-(1H-indol-3-yl)ethyl!piperazine hydrochloride

mp: 155° C. (dec.)

α!_(D) ²⁶ : -3.0° (C=1.0, MeOH)

IR (Nujol): 3700-3100, 2800-2100, 1635, 1276, 1170, 1130 cm⁻¹

NMR (DMSO-d₆, δ): 2.73-4.15 (12H, m); 4.75-5.25 (1H, m); 7.01-8.24 (13H,m); 11.00 (1H, s); 11.30 (1H, br s)

MASS: 560 (M+1) (free), 417

10) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(4-phenoxybutyl)piperazinehydrochloride

mp: 153°-156° C.

α!_(D) ²⁶ : +0.5° (C=1.0, MeOH)

IR (Nujol): 3600-3100, 2700-2000, 1640, 1280, 1122, 903 cm⁻¹

NMR (DMSO-d₆, δ): 1.70-2.15 (4H, m); 2.80-4.15 (12H, m); 4.55-5.20 (1H,m); 6.94-8.23 (13H, m)

MASS: 565 (M+1) (free)

11) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(3-phenoxypropyl)piperazinehydrochloride

mp: 84°-87° C.

α!_(D) ²⁶ : -0.2° (C=1.0, MeOH)

IR (Nujol): 3600-3100, 2700-2000, 1635, 1275, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.20-2.40 (2H, m); 2.80-4.20 (12H, m); 4.50-5.20 (1H,m); 6.90-7.70 (12H, m); 8.17-8.23 (1H, m); 11.00-11.30 (1H, m)

MASS: 551 (M+1) (free)

12) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(2-phenoxyethyl)piperazinehydrochloride

mp: 145°-148° C.

α!_(D) ²⁶ : -6.4° (C=1.0, MeOH)

IR (Nujol): 3700-3100, 2750-2000, 1635, 1275, 1125, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.85-5.20 (13H, m); 6.97-7.74 (12H, m); 8.18-8.23 (1H,m)

MASS: 537 (M+1) (free)

13) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-3-(1H-indol-3-yl)propyl!piperazine hydrochloride

mp: 163° C. (dec.)

α!_(D) ²⁷ : +1.4° (C=1.0, MeOH)

IR (Nujol): 3600-3100, 2700-2000, 1634, 1275, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.10-2.35 (2H, m); 2.70-5.20 (13H, m); 6.90-7.80 (12H,m); 8.15-8.22 (1H, m); 10.80-11.30 (2H, m)

MASS: 574 (M+1) (free), 417

14) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4- (4-fluoro-2-methoxybenzoyl)methyl!piperazine hydrochloride

mp: 176°-180° C.

α!_(D) ²⁴ : +5.5° (C=1.0, MeOH)

IR (Nujol): 3600-3100, 2800-2100, 1650, 1605, 1280, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.73-5.20 (14H, m); 6.94-8.30 (11H, m)

MASS: 583 (M+1) (free), 417

15) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-4-methyl-2-(N-methyl-1H-indol-3-yl-methyl)piperazine

IR (CHCl₃): 2930, 2830, 2780, 1683 cm⁻¹

NMR (DMSO-d₆, δ): 1.78-2.44 (2H, m); 2.24 (3H, s); 2.64-3.97 (6H, m);3.69 and 3.72 (3H, 2 s); 4.17-4.96 (1H, m); 6.64-8.30 (8H, m)

MASS: 484 (M+1)

Example 13 ##STR32##

To an ice-cooled mixture of (2R)-2-benzyl-1-3,5-bis(trifluoromethyl)benzoyl!piperazine (0.3 g) and potassiumcarbonate (0.20 g) in dimethylformamide (3 ml) was added a solution of3-chloro-1-phenyl-1-propane (0.18 g) in dimethylformamide (1 ml) undernitrogen atmosphere. The resulting mixture was stirred at the sametemperature for 1.5 hours and then at room temperature for 30 minutes.The mixture was poured into a mixture of water and ethyl acetate. Theorganic layer was separated, washed with brine and evaporated. Theresidue was purified by chromatography on a silica gel (toluene/ethylacetate=30:1) to afford object compound, which was converted to thecorresponding hydrochloride, (2R)-2-benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(2-benzoylethyl)piperazinehydrochloride, by treatment with 4N hydrogen chloride in ethyl acetatesolution.

mp: 218°-220° C.

α!_(D) ²⁶ : +7.2° (C=1.0, DMF)

IR (Nujol): 2400, 1680, 1640, 1277, 1122, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.80-4.20 (12H, m); 4.50-5.20 (1H, m); 6.90-7.00 (1H,m); 7.10-7.45 (5H, m); 7.50-7.80 (4H, m); 8.00-8.10 (2H, m); 8.10-8.25(1H, m); 10.55-11.10 (1H, m)

MASS: 549 (M+1) (free), 417

Example 14

To an ice-cooled mixture of (2R)-2-benzyl-1-3,5-bis(trifluoromethyl)benzoyl!piperazine (0.3 g) and triethylamine(0.39 ml) in dimethylformamide (8 ml) was added 3-(chloromethyl)pyridinehydrochloride (0.12 g). The reaction mixture was stirred at the sametemperature for 30 minutes and then at room temperature for 2 hours.Additional triethylamine (0.39 ml) and 3-(chloromethyl)pyridinehydrochloride (0.12 g) were added and the resulting mixture was stirredovernight. The reaction mixture was filtered and the filtrate wasconcentrated and subjected to a chromatography on a silica gel elutingwith a mixture of toluene and ethyl acetate (5:1). The eluent wastreated with 4N hydrogen chloride in ethyl acetate solution to give(2R)-2-benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(pyridin-3-yl-methyl)piperazinedihydrochloride.

mp: 164°-168° C.

α!_(D) ²⁵ : +9.1° (C=1.0, MeOH)

IR (Nujol): 3700-3100, 2700-2000, 1630, 1270, 1120, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.80-5.40 (11H, m); 6.85-6.90 (1H, m); 7.10-7.40 (4H,m); 7.46 (1H, s); 7.75 (1H, s); 7.90-8.00 (1H, m); 8.19-8.23 (1H, m);8.66-8.70 (1H, m); 8.88-8.91 (1H, m); 9.09 (1H, s)

MASS: 508 (M+1) (free)

Example 15

The following compounds were obtained according to a similar manner tothat of Example 14.

1) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(methoxycarbonylmethyl)piperazine

IR (Neat): 3700-3300, 2940, 1740, 1637, 1430, 1270, 1120, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.30-5.00 (14H, m); 6.90-7.00 (1H, m); 7.10-7.70 (6H,m); 8.10-8.20 (1H, m)

MASS: 489 (M+1), 417

2) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(methoxycarbonylmethyl)piperazine

α!_(D) ²⁴ : -8.3° (C=1.0, MeOH)

IR (Neat): 3300, 1737, 1628, 1276, 1130, 900, 737 cm⁻¹

NMR (DMSO-d₆, δ): 2.30-5.00 (14H, m); 6.60-8.20 (8H, m); 10.87 (1H, s)

MASS: 528 (M+1)

3) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(methoxycarbonylmethyl)piperazine

IR (Neat): 3000-2700, 1745, 1645, 1500, 1430, 1380, 1350, 1330 cm⁻¹

NMR (CDCl₃, δ): 2.1-2.3 (6H, m), 2.4-3.8 (10H, m); 3.74 (3H, s); 4.5-5.2(1H, m); 6.6-7.5 (5H, m); 7.8-7.9 (1H, m)

MASS: 517 (M+1), 445

Example 16 ##STR33##

To a stirred mixture of (2R)-2-benzyl-1-3,5-bis(trifluoromethyl)benzoyl!piperazine (0.3 g) and2-(1H-indol-3-yl)acetic acid (0.13 g) in dichloromethane (8 ml)containing triethylamine (0.25 ml) was added 2-chloro-1-methylpyridiniumiodide (0.22 g) at room temperature under nitrogen atmosphere. Afterbeing stirred for 5 hours, the reaction mixture was diluted withdichloromethane and washed with 0.1N hydrochloric acid, aqueoussaturated sodium bicarbonate solution and brine, and dried overmagnesium sulfate. After removal of the solvent, the residue waspurified by column chromatography on silica gel usingchloroform-methanol (50:1) as eluent to give (2R)-2-benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4- 2-(1H-indol-3-yl)acetyl!piperazine(0.34 g) as a white powder.

mp: 201°-210° C.

α!_(D) ²⁷ : +27.6° (C=1.0, MeOH)

IR (Nujol): 3270, 1630, 1276, 1115, 900, 737 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.00 (11H, m); 6.70-7.70 (12H, m); 8.10-8.20 (1H,m); 10.85-11.10 (1H, m)

MASS: 574 (M+1), 417

Example 17

The following compounds were obtained according to a similar manner tothat of Example 16.

1) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(trans-cinnamoyl)piperazine

mp: 118°-119° C.

α!_(D) ²⁵ : -34.7° (C=1.0, MeOH)

IR (Nujol): 3550-3100, 1635, 1275, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.80-5.20 (11H, m); 6.50-8.20 (14H m)

MASS: 586 (M+1), 452

2) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4-fluoro-trans-cinnamoyl)piperazine

mp: 116°-120° C.

α!_(D) ²⁶ : -31.5° (C=1.0, MeOH)

IR (Nujol): 3500-3100, 1635, 1595, 1277, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.80-5.15 (10H, m); 6.50-8.30 (12H, m); 10.80-10.95(1H, m)

MASS: 604 (M+1)

3) (2R)-1- 3,5-Bis(trifluromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-2-(N,N-dimethylamino)acetyl!-piperazine

IR (Nujol): 3200, 1655, 1635 cm⁻¹

NMR (DMSO-d₆, δ): 2.10-2.50 (6H, m); 2.74-4.65 and 4.80-5.15 (11H, 2 m),6.54-7.55 (5H, m); 7.60-8.30 (3H, m); 10.92 (1H, s)

MASS: 541 (M+1)

4) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(3-phenylpropionyl)piperazine

α!_(D) ²⁵ : +14.1° (C=1.0, MeOH)

IR (Neat): 3700-3300, 3000, 2800, 1630, 1420, 1270, 1120, 900, 695 cm⁻¹

NMR (DMSO-d₆, δ): 2.50-5.10 (13H, m); 6.85-6.95 (1H, m); 7.10-7.45 (10H,m); 7.59-7.68 (1H, m); 8.12-8.18 (1H, m)

MASS: 549 (M+1), 417

5) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(4-phenylbutyryl)piperazine

α!_(D) ²⁷ : +13.3° (C=1.0, MeOH)

IR (Neat): 3700-3300, 3010, 2920, 1640, 1420, 1270, 1122, 900, 695 cm⁻¹

NMR (DMSO-d₆, δ): 1.80-1.95 (2H, m); 2.60-4.50 (13H, m); 6.90-7.80 (12H,m); 8.10-8.20 (1H, m)

MASS: 563 (M+1), 417

6) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(5-phenylvaleryl)piperazine

α!_(D) ²⁷ : +13.1° (C=1.0, MeOH)

IR (Neat): 3700-3300, 3010, 2820, 1635, 1425, 1275, 1125, 900, 695 cm⁻¹

NMR (DMSO-d₆, δ): 1.50-1.70 (4H, m); 2.60-4.50 (13H, m); 6.90-7.80 (12H,m); 8.10-8.20 (1H, m)

MASS: 577 (M+1), 417

7) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(trans-cinnamoyl)piperazine

mp: 144°-145° C.

α!_(D) ²⁸ : +13.90° (C=1.0, MeOH)

IR (Nujol): 3700-3100, 1634, 1607, 1281, 1184, 1128, 905 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (11H, m); 6.80-7.80 (12H, m); 8.14-8.20 (1H,m)

MASS: 547 (M+1), 417

8) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-2-(4-fluorophenyl)acetyl!piperazine

α!_(D) ²⁷ : +14.9° (C=1.0, MeOH)

IR (Neat): 3700-3300, 3020, 2900, 1630, 1508, 1425, 1270, 1125, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (11H, m); 6.85-7.00 (1H, m); 7.10-7.75 (10H,m); 8.10-8.22 (1H, m)

MASS: 553 (M+l), 417

9) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-(1H-indol-3-yl)carbonyl!piperazine

mp: 130°-131° C.

α!_(D) ²⁸ : +31.8° C. (C=1.0, MeOH)

IR (Nujol): 3550-3000, 1670-1570, 1275, 1130, 995, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.90-5.00 (9H, m); 6.80-8.30 (13H, m); 11.66 (1H, brs)

MASS: 560 (M+1), 417

10) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-3-(1H-indol-3-yl)propionyl!piperazine

mp: 93°-95° C.

α!_(D) ²⁸ : -30.6° (C=1.0, MeOH)

IR (Nujol): 3450-3100, 1630, 1275, 1130, 900, 739 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.00 (13H, m); 6.80-7.70 (12H, m); 8.12-8.18 (1H,m); 10.82 (1H, s)

MASS: 588 (M+1), 417

11) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-4-(1H-indol-3-yl)butyryl!piperazine

mp: 88°-90° C.

α!_(D) ²⁸ : +11.0° (C=1.0, MeOH)

IR (Nujol): 3400-3100, 1630, 1275, 1130, 900, 737 cm⁻¹

NMR (DMSO-d₆, δ): 1.85-2.10 (2H, m); 2.30-5.10 (13H, m); 6.90-7.75 (12H,m); 8.10-8.20 (1H, m); 10.77 (1H, s)

MASS: 602 (M+1), 417

12) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-(3-phenyl)propioloyl!piperazine

mp: 177-179° C.

α!_(D) ²⁵ : +10.80 (C=1.0, MeOH)

IR (Nujol): 2200, 1630, 1610, 1284, 1129, 906 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.15 (9H, m); 6.95-7.80 (12H, m); 8.10-8.25 (1H,m)

MASS: 545 (M+1), 417

13) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(3-cyclohexylpropionyl)piperazine

α!_(D) ²⁵ : +12.9° (C=1.0, MeOH)

IR (Neat): 3700-3300, 1635, 1272, 1126, 1005, 900, 700 cm⁻¹

NMR (DMSO-d₆, δ): 0.80-1.05 (2H, m);

1.05-1.38 (4H, m); 1.38-1.60 (2H, m);

1.60-1.85 (5H, m); 2.20-5.05 (11H, m);

6.90-7.05 (1H, m); 7.10-7.80 (6H, m); 8.10-8.20 (1H, m)

MASS: 555 (M+1), 417

14) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-2(E)-benzylidenepropionyl!piperazine

mp: 69°-73° C.

α!_(D) ²⁵ : +9.1° (C=1.0, MeOH)

IR (Neat): 3700-3300, 1620, 1274, 1125, 1008, 903, 697 cm⁻¹

NMR (DMSO-d₆, δ): 2.06 (3H, s); 2.60-5.10 (9H, m); 6.62 (1H, s);6.95-7.05 (1H, m); 7.15-7.80 (11H, m); 8.10-8.20 (1H, m)

MASS: 561 (M+1), 417

15) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-3-(1H-indol-3-yl)-trans-acryloyl!piperazine

mp: 125° C. (dec.)

α!_(D) ²⁴ : +19.0° (C=1.0, MeOH)

IR (Nujol): 3500-3000, 1642, 1575, 1277, 1133, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (9H, m); 6.90-8.30 (15H, m); 11.66 (1H, s)

MASS: 586 (M+1), 417

16) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(4-methyl-trans-cinnamoyl)piperazine

mp: 152°-153° C.

α!_(D) ²⁴ : +12.4° (C=1.0, MeOH)

IR (Nujol): 1634, 1604, 1510, 1286, 1185, 1128, 904 cm⁻¹

NMR (DMSO-d₆, δ): 2.34 (3H, s); 2.60-5.10 (9H, m); 6.80-7.80 (13H, m);8.14-8.20 (1H, m)

MASS: 561 (M+1), 417

17) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(4-methoxy-trans-cinnamoyl)piperazine

mp: 133°-134° C.

α!_(D) ²⁴ : +12.5° (C=1.0, MeOH)

IR (Nujol): 1634, 1600, 1510, 1284, 1186, 1128, 903 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (12H, m); 6.96-7.80 (13H, m); 8.14-8.20 (1H,m)

MASS: 577 (M+1), 417

18) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(4-chloro-trans-cinnamoyl)piperazine

mp: 135°-136° C.

α!_(D) ²⁴ : +11.0° (C=1.0, MeOH)

IR (Nujol): 1633, 1601, 1490, 1275, 1175, 1035, 898 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (9H, m); 6.80-7.85 (13H, m); 8.14-8.20 (1H,m)

MASS: 581 (M+1), 417

19) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(4-N,N-dimethylamino-trans-cinnamoyl)piperazine

mp: 114°-118° C.

α!_(D) ²⁴ : +12.1° (C=1.0, MeOH)

IR (Nujol): 1634, 1605, 1521, 1280, 1170, 1127 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (15H, m); 6.70-6.74 (2H, m); 6.95-7.73 (11H,m); 8.14-8.20 (1H, m)

MASS: 590 (M+1), 417

20) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(4-phenyl-trans-cinnamoyl)piperazine

mp: 159-160° C.

α!_(D) ²⁴ : +9.9° (C=1.0, MeOH)

IR (Nujol): 1640, 1601, 1282, 1180, 1130, 906 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (9H, m); 6.85-7.95 (18H, m); 8.14-8.20 (1H,m)

MASS: 623 (M+1)

21) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(4-fluoro-trans-cinnamoyl)piperazine

mp: 114°-116° C.

α!_(D) ²⁴ : +13.60° (C=1.0, MeOH)

IR (Nujol): 1630, 1608, 1508, 1283, 1190, 1127, 905 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (9H, m); 6.80-7.90 (13H, m); 8.14-8.19 (1H,m)

MASS: 565 (M+1), 417

22) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(4-trifluoromethyl-trans-cinnamoyl)piperazine

mp: 124°-126° C.

α!_(D) ²⁴ : +12.9° (C=1.0, MeOH)

IR (Nujol): 1628, 1610, 1274, 1200, 1125, 905 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (9H, m); 6.85-8.10 (13H, m); 8.14-8.20 (1H,m)

MASS: 615 (M+1), 417

23) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-1-oxo-5-phenyl-2(E),4(E)-pentadienyl!piperazine

mp: 103°-105° C.

α!_(D) ²⁴ : +17.1° (C=1.0, MeOH)

IR (Nujol): 1631, 1600, 1285, 1184, 1130, 996, 902 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.15 (9H, m); 6.70-7.80 (16H, m); 8.13-8.19 (1H,m)

MASS: 573 (M+1), 417

24) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(4-nitro-trans-cinnamoyl)piperazine

mp: 141°-144° C.

α!_(D) ²⁵ : +14.0° (C=1.0, MeOH)

IR (Nujol): 1645, 1610, 1510, 1350, 1327, 1280, 1177, 1128, 903 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (9H, m); 6.80-8.30 (14H, m)

MASS: 592 (M+1), 417

25) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-3-(3-pyridyl)-trans-acryloyl!piperazine

mp: 139°-141° C.

α!_(D) ²⁵ : +14.2° (C=1.0, MeOH)

IR (Nujol): 1632, 1608, 1280, 1190, 1125, 905 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (9H, m); 6.80-7.80 (10H, m); 8.14-8.19 (2H,m); 8.56 (1H, s); 8.90 (1H, s)

MASS: 548 (M+1), 417

26) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-3-(3-furyl)-trans-acryloyl!piperazine

mp: 83°-85° C.

α!_(D) ²⁵ : +11.8° (C=1.0, MeOH)

IR (Nujol): 1635, 1605, 1278, 1179, 1134, 902 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (9H, m); 6.90-8.20 (13H, m)

MASS: 537 (M+1), 417

27) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(3-phenylpropionyl)piperazine

α!_(D) ²⁶ : -4.8° (C=1.0, MeOH)

IR (Neat): 3450, 3050-2800, 1630, 1500, 1430, 1350, 1340 cm⁻¹

NMR (CDCl₃, δ): 2.1-2.3 (6H, m); 2.4-3.5 (11H, m); 3.6-4.1 (1H, m);4.4-5.3 (1H, m); 6.5-7.5 (10H, m); 7.8-7.9 (1H, m)

MASS: 577 (M+1), 445

28) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-(3-benzoyl-trans-acryloyl)piperazine

mp: 110°-118° C.

α!_(D) ²² : +19.1° (C=1.0, MeOH)

IR (Nujol): 1636, 1280, 1181, 1130, 904 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (9H, m); 6.80-8.25 (15H, m)

MASS: 575 (M+1), 417

29) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-4-phenyl-3(E)-butenoyl!piperazine

mp: 85°-87° C.

α!_(D) ²² : +19.5° (C=1.0, MeOH)

IR (Nujol): 1635, 1285, 1189, 1126, 903 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.15 (11H, m); 6.30-6.60 (2H, m); 6.90-7.65 (12H,m); 8.13-8.20 (1H, m)

MASS: 561 (M+1), 417

30) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-3-(2-thienyl)-trans-acryloyl!piperazine

mp: 118°-122° C.

α!_(D) ²² : +16.3° (C=1.0, MeOH)

IR (Nujol): 1633, 1499, 1281, 1183, 1127, 905 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (9H, m); 6.80-7.15 (2H, m); 7.15-7.85 (10H,m); 8.14-8.20 (1H, m)

MASS: 553 (M+1), 417

31) (2R)-4- 3-2-(N-Acetylamino)thiazol-4-yl!-trans-acryloyl!-2-benzyl-1-3,5-bis(trifluoromethyl)-benzoyl!piperazine

mp: 90°-94° C.

α!_(D) ²² : +11.3° (C=0.5, MeOH)

IR (Nujol): 1635, 1540, 1278, 1175, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.16 (3H, s); 2.60-4.60 (9H, m); 6.15-6.39 (1H, m);6.98-7.80 (9H, m); 8.14-8.20 (1H, m); 12.28 (1H, br s)

MASS: 611 (M+1), 391

32) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(4-hydroxy-trans-cinnamoyl)piperazine

mp: 103°-105° C.

α!_(D) ²⁶ : +12.3° (C=1.0, MeOH)

IR (Nujol): 3550-3000, 1636, 1600, 1511, 1277, 1130, 903 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.15 (9H, m); 6.16-6.39 (1H, m); 6.78-7.80 (12H,m); 8.14-8.20 (1H, m); 9.88 (1H, s)

MASS: 563 (M+1), 417

33) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(2-naphthoyl)piperazine

mp: 87°-90° C.

α!_(D) ²² : +21.8° (C=1.0, MeOH)

IR (Nujol): 1635, 1276, 1175, 1129, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-4.70 (9H, m); 6.70-8.25 (15H, m)

MASS: 571 (M+1), 417

34) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(2-methoxy-trans-cinnamoyl)piperazine

mp: 104°-106° C.

α!_(D) ²⁶ : +12.9° (C=1.0, MeOH)

IR (Nujol): 1634, 1610, 1287, 1184, 1128, 905 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (12H, m); 6.85-7.95 (13H, m); 8.14-8.20 (1H,m)

MASS: 577 (M+1), 417

35) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4-nitro-trans-cinnamoyl)piperazine

mp: 128°-131° C.

α!_(D) ²² : -32.3° (C=1.0, MeOH)

IR (Nujol): 3260, 1637, 1608, 1516, 1277, 1175, 1140, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.80-5.20 (9H, m); 6.50-8.35 (14H, m); 10.87 (1H, brs)

MASS: 631 (M+1)

36) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(3-cyclohexylpropionyl)piperazine

mp: 190°-192° C.

α!_(D) ²⁶ : -4.5° (C=1.0, MeOH)

IR (Nujol): 3280, 1649, 1627, 1276, 1170, 1130, 898 cm⁻¹

NMR (DMSO-d₆, δ): 0.60-1.80 (11H, m); 2.20-5.20 (13H, m); 6.60-8.30 (8H,m); 10.88 (1H, s)

MASS: 594 (M+1)

37) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(2-methoxyacetyl)piperazine

α!_(D) ²⁴ : +13.0° (C=1.0, MeOH)

IR (Neat): 3650-3200, 1635, 1275, 1125, 903, 700 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (14H, m); 6.90-7.75 (7H, m); 8.10-8.20 (1H,m)

MASS: 489 (M+1), 417

38) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-3-(3-pyridyl)-trans-acryloyl!- piperazine

mp: 81°-85° C.

α!_(D) ²¹ : -2.1° (C=1.0, MeOH)

IR (Nujol): 1635, 1610, 1450, 1350, 1320 cm⁻¹

NMR (CDCl₃, δ): 2.17 and 2.22 (6H, 2 s); 2.6-5.3 (9H, m); 6.4-8.0 (10H,m); 8.60 (1H, d, J=4.2 Hz); 8.7-8.9 (1H, m)

39) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-4-(4-chloro-trans-cinnamoyl)-2-(3,4-dimethylbenzyl)piperazine

mp: 68°-70° C.

α!_(D) ²³ : -3.6° (C=1.0, MeOH)

IR (Nujol): 1645, 1605, 1490, 1450, 1370, 1350, 1320 cm⁻¹

NMR (CDCl₃, δ): 2.0-2.3 (6H, m); 2.6-3.5 (5H, m); 3.6-4.3 (2H, m);4.6-5.3 (2H, m); 6.5-8.0 (12H, m)

MASS: 609 (M+1)

40) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(4-fluoro-trans-cinnamoyl)piperazine

mp: 78°-80° C.

α!_(D) ²³ : -3.5° (C=1.0, MeOH)

IR (Nujol): 1645, 1600, 1350, 1320 cm⁻¹

NMR (CDCl₃, δ): 2.0-2.3 (6H, m); 2.6-3.5 (5H, m); 3.6-4.3 (2H, m);4.6-5.3 (2H, m); 6.5-8.0 (12H, m)

MASS: 593 (M+1), 445

41) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(4-nitro-trans-cinnamoyl)piperazine

mp: 101°-105° C.

α!_(D) ²³ : -3.3° (C=1.0, MeOH)

IR (Nujol): 1645, 1610, 1515, 1340, 1320 cm⁻¹

NMR (CDCl₃, δ): 2.0-2.3 (6H, m); 2.6-3.5 (5H, m); 3.6-4.5 (2H, m);4.6-5.4 (2H, m); 6.6-8.0 (9H, m); 8.2-8.4 (3H, m)

MASS: 620 (M+1)

42) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-4-3-cyclohexylpropionyl)-2-(3,4-dimethylbenzyl)piperazine

α!_(D) ²⁴ : -5.5° (C=1.0, MeOH)

IR (Neat): 1635, 1500, 1430, 1380, 1350, 1320 cm⁻¹

NMR (CDCl₃, δ): 0.8-1.9 (13H, m); 2.1-3.1 (13H, m); 3.2-3.5 (2H, m);3.7-4.2 (1H, m); 4.4-5.3 (1H, m); 6.5-7.5 (5H, m); 7.8-7.9 (1H, m)

MASS: 583 (M+1)

43) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-2-(3-pyridyl)acetyl!piperazine hydrochloride

α!_(D) ²² : +22.2° (C=1.0, MeOH)

IR (Neat): 3700-3100, 2700-2100, 1620, 1270, 1120, 901 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.20 (11H, m); 6.90-8.88 (12H, m)

MASS: 536 (M+1) (free), 417

44) (2R)-4-(Benzofuran-2-yl-carbonyl)-2-benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!piperazine

mp: 143°-145° C.

α!_(D) ²² : +7.3° (C=1.0, MeOH)

IR (Nujol): 1634, 1565, 1274, 1170, 1127, 894 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.15 (9H, m); 6.90-7.80 (12H, m); 8.15-8.21 (1H,m)

MASS: 561 (M+1)

45) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-(3-pyridyl)carbonyl!piperazine hydrochloride

α!_(D) ²² : +17.8° (C=1.0, MeOH)

IR (Neat): 3700-3150, 2800-2100, 1630, 1275, 1125, 902 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.20 (9H, m); 6.80-7.50 (6H, m); 7.60-8.00 (2H,m); 8.10-8.55 (2H, m); 8.85-9.15 (2H, m)

MASS: 522 (M+1) (free), 417

46) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-4-(4-chloro-trans-cinnamoyl)-2-(1H-indol-3-yl-methyl)piperazine

mp: 125°-138° C.

α!_(D) ²⁴ : -34.8° (C=1.0, MeOH)

IR (Nujol): 3450-3100, 1638, 1605, 1277, 1175, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.15 (9H, m); 6.60-8.25 (14H, m); 10.80-11.00(1H, m)

MASS: 620 (M+1)

47) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-4-(3-fluoro-trans-cinnamoyl)-2-(1H-indol-3-yl-methyl)piperazine

mp: 120°-130° C.

α!_(D) ²⁴ : -32.2° (C=1.0, MeOH)

IR (Nujol): 3500-3100, 1635, 1605, 1275, 1175, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.70-5.20 (9H, m); 6.50-8.20 (14H, m); 10.87 (1H, s)

MASS: 604 (M+1)

48) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-4-(2-fluoro-trans-cinnamoyl)-2-(1H-indol-3-yl-methyl)piperazine

mp: 110°-114° C.

α!_(D) ²⁴ : -29.8° (C=1.0, MeOH)

IR (Nujol): 3500-3100, 1637, 1608, 1276, 1175, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.80-5.20 (9H, m); 6.50-8.25 (14H, m); 10.87 (1H, s)

MASS: 604 (M+1)

49) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-4-(3-cyclo-pentylpropionyl)-2-(1H-indol-3-yl-methyl)piperazine

mp 180°-183° C.

α!_(D) ²⁰ : -2.9° (C=1.0, MeOH)

IR (Nujol): 3280, 1650, 1628, 1277, 1212, 1170, 1131, 900 cm⁻¹

NMR (DMSO-d₆, δ): 0.85-1.35 (2H, m); 1.40-2.00 (9H, m); 2.20-5.15 (11H,m); 6.60-8.25 (8H, m); 10.88 (1H, s)

MASS: 580 (M+1)

50) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-4-(3-cyclo-hexyl)-trans-acryloyl!-2- (1H-indol-3-yl-methyl)-piperazine

mp: 198°-200° C.

α!_(D) ²⁴ : -19.0° (C=0.1, MeOH)

IR (Nujol): 3280, 1655, 1628, 1275, 1170, 1132, 900, 750 cm⁻¹

NMR (DMSO-d₆, δ): 0.65-1.25 (5H, m); 1.35-2.15 (6H, m); 2.55-5.00 (9H,m); 5.85-8.10 (10H, m); 10.60-10.80 (1H, m)

MASS: 592 (M+1)

51) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-4-(4-fluorobenzoyl)-2-(1H-indol-3-yl-methyl)piperazine

mp: 164°-165° C.

IR (Nujol): 3280, 1626, 1510 cm⁻¹

NMR (DMSO-d₆, δ): 2.55-5.05 (9H, m); 6.45-8.25 (12H, m); 10.84 (1H, s)

MASS: 578 (M+1)

52) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(3-nitro-trans-cinnamoyl)piperazine

mp: 127°-133° C.

α!_(D) ²⁴ : -19.6° (C=1.0, MeOH)

IR (Nujol): 3450-3100, 1635, 1608, 1527, 1276, 1175, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.80-5.20 (9H, m); 6.55-8.80 (14H, m); 10.80-11.00(1H, m)

MASS: 631 (M+1)

53) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(2-nitro-trans-cinnamoyl)piperazine

mp: 125°-133° C.

α!_(D) ²⁴ : -18.9° (C=1.0, MeOH)

IR (Nujol): 3450-3100, 1637, 1607, 1520, 1278, 1175, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.80-5.20 (9H, m); 6.55-8.30 (14H, m); 10.80-10.95(1H, m)

MASS: 631 (M+1), 456

54) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(3-pyridyl)carbonyl!piperazine hydrochloride

mp: 150°-160° C.

α!_(D) ²⁴ : +1.7° (C=1.0, MeOH)

IR (Nujol): 3650-3100, 2800-2000, 1625, 1280, 1180, 1127, 903 cm⁻¹

NMR (DMSO-d₆, δ): 2.80-5.20 (9H, m); 6.40-9.20 (12H,m)

MASS: 561 (M+1) (free)

55) (2R)-4- 2-(Benzoylamino)acetyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

mp: 123°-135° C.

α!_(D) ²⁴ : -6.6° (C=0.5, MeOH)

IR (Nujol): 3600-3100, 1636, 1278, 1175, 1133, 903 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.20 (11H, m); 6.55-8.21 (13H, m); 8.65-8.75 (1H,m); 10.80-11.00 (1H, m)

MASS: 617 (M+1), 456

56) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-4-(cyclo-propylcarbonyl)-2-(1H-indol-3-yl-methyl)piperazine

mp: 109°-114° C.

α!_(D) ²⁰ : -8.2° (C=1.0, MeOH)

IR (Nujol): 3500-3100, 1630, 1276, 1175, 1130, 902 cm⁻¹

NMR (DMSO-d₆, δ): 0.78 (4H, br s), 2.60-5.20 (10H, m); 6.60-8.25 (8H,m); 10.87 (1H, s)

MASS: 524 (M+1)

57) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-3-(3-pyridyl)-trans-acryloyl!-piperazine

mp: 86.5°-89.5° C.

α!_(D) ²⁴ : -25.0° (C=1.0, MeOH)

IR (Nujol): 3600-3100, 1637, 1278, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.70-5.20 (9H, m); 6.15-8.35 (12H, m); 8.50-8.62 (1H,m); 8.75-9.05 (1H, m); 10.85-10.90 (1H, m)

MASS: 587 (M+1), 457

58) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-4-trifluoromethyl-trans-cinnamoyl!piperazine

mp: 74°-76° C.

α!_(D) ²¹ : -2.3° (C=1.0, MeOH)

IR (Nujol): 1640, 1610, 1500, 1440, 1350, 1330 cm⁻¹

NMR (CDCl₃, δ): 2.12 and 2.22 (6H, 2 s); 2.7-5.3 (9H, m); 6.6-8.0 (12H,m)

MASS: 643 (M+1), 473, 455

59) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(phenylpropioloyl)piperazine

mp: 72°-74° C.

α!_(D) ²¹ : +1.2° (C=1.0, MeOH)

IR (Nujol): 2200, 1625, 1490, 1450, 1350, 1320 cm⁻¹

NMR (CDCl₃, δ): 2.1-2.3 (6H, m); 2.6-5.4 (9H, m); 6.6-7.9 (11H, m)

MASS: 573 (M+1), 445

60) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(3-cyclohexyl-trans-acryloyl)piperazine

mp: 78°-83° C.

α!_(D) ²¹ : -5.3° (C=1.0, MeOH)

IR (Nujol): 1640, 1620, 1500, 1430, 1340, 1320 cm⁻¹

NMR (CDCl₃, δ): 1.0-1.5 (5H, m); 1.6-1.9 (5H, m); 2.0-2.3 (7H, m);2.5-5.3 (9H, m); 6.0-7.6 (7H, m); 7.87 (1H, br s)

MASS: 581 (M+1)

61) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(3-pyridylcarbonyl)piperazinehydrochloride

mp: 98°-100° C.

α!_(D) ²⁴ : +2.3° (C=1.0, MeOH)

IR (Neat): 2700-2300, 1635, 1500, 1430, 1370, 1350, 1340, 1330 cm⁻¹

NMR (DMSO-d₆, δ): 2.0-2.3 (6H, m); 2.8-5.2 (9H, m); 6.4-9.1 (11H, m)

MASS: 550 (M+1) (free)

Example 18 ##STR34##

To a stirred solution of (2R)-2-benzyl-1-3,5-bis(trifluoromethyl)benzoyl!piperazine (0.3 g) in drydimethylformamide (3 ml) containing dry pyridine (0.06 ml) was added asolution of 2-phenoxyacetyl chloride (0.12 g) in dry dimethylformamide(1 ml) at 0° C., and the mixture was stirred at the same temperature for30 minutes and then at room temperature for 30 minutes. Additionalpyridine (0.02 ml) and a solution of 2-phenoxyacetyl chloride (0.025 g)in dry dimethylformamide (0.3 ml) were added to the reaction mixture.After being stirred for 30 minutes, the mixture was poured into water(43 ml) and extracted with ethyl acetate. The extract was washed withbrine and dried over magnesium sulfate. After evaporation of thesolvent, the residue was purified by a silica gel column chromatography.Elution with toluene-ethyl acetate afforded (2R)-2-benzyl-l-3,5-bis(trifluoromethyl)benzoyl!-4-(2-phenoxyacetyl)piperazine (0.34 g)as a white powder.

α!_(D) ²⁵ : +28.9° (C=1.0, MeOH)

IR (Neat): 3700-3100, 1635, 1274, 1170, 1126, 900, 748 cm⁻¹

NMR (DMSO-d₆, δ): 2.80-5.20 (11H, m); 6.90-7.70 (12H, m); 8.12-8.22 (1H,m)

MASS: 551 (M+l), 417

Example 19

The following compounds were obtained according to a similar manner tothat of Example 18.

1) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(N,N-dimethylaminocarbonyl)piperazine

IR (Nujol): 3230, 1621 cm⁻¹

NMR (DMSO-d₆, δ): 2.73 (1H, s); 2.82 (6H, s); 2.89 (1H, s); 2.70-4.98(7H, m); 6.55-7.40 (5H, m); 7.40-8.24 (3H, m); 10.86 (1H, s)

MASS: 527 (M+1)

2) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-mesylpiperazine

mp: 165°-166° C.

α!_(D) ²⁶ : +7.5° (C=1.0, MeOH)

IR (Nujol): 1652, 1325, 1282, 1165, 1128, 904, 790 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (12H, m); 6.95-7.05 (1H, m); 7.10-7.80 (6H,m); 8.15-8.25 (1H, m)

MASS: 495 (M+1), 417

3) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(2-phenylacetyl)piperazine

mp: 60°-65° C.

α!_(D) ²⁶ : +14.1° (C=1.0, MeOH)

IR (Neat): 3700-3200, 1635, 1275, 1175, 1125, 900, 700 cm⁻¹

NMR (DMSO-d₆, δ): 2.70-5.10 (11H, m); 6.80-7.00 (1H, m); 7.10-7.70 (11H,m); 8.10-8.20 (1H, m)

MASS: 535 (M+1), 417

4) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(N,N-dimethylcarbamoyl)piperazine

α!_(D) ²⁷ : -22.6° (C=1.0, MeOH)

IR (Neat): 3700-3300, 2900, 1630, 1490, 1430, 1275, 1125, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (15H, m); 6.90-7.00 (1H, m); 7.10-7.75 (6H,m); 7.90-8.20 (1H, m)

MASS: 488 (M+1), 445

5) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-acetylpiperazine

α!_(D) ²⁵ : +10.0° (C=1.0, MeOH)

IR (Neat): 3700-3150, 1635, 1275, 1125, 900, 700 cm⁻¹

NMR (DMSO-d₆, δ): 2.03-2.16 (3H, m); 2.60-5.10 (9H, m); 6.90-8.25 (8H,m)

MASS: 459 (M+1), 417

6) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(trifluoromethylcarbonyl)piperazine

mp: 57°-62° C.

α!_(D) ²⁶ : +10.3° (C=1.0, MeOH)

IR (Nujol): 1690, 1636, 1277, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.20 (9H, m); 6.90-8.30 (8H, m)

MASS: 513 (M+1), 417

7) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-propionylpiperazine

mp: 52°-56° C.

α!_(D) ²⁶ : +11.3° (C=1.0, MeOH)

IR (Neat): 3700-3400, 1630, 1275, 1125, 1053, 1000, 903, 700 cm⁻¹

NMR (DMSO-d6, o): 0.99-1.10 (3H, m); 2.30-5.10 (11H, m); 6.90-7.05 (1H,m); 7.10-7.75 (6H, m); 8.10-8.25 (1H, m)

MASS: 473 (M+1), 417

8) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-2(E)-butenoyl!piperazine

α!_(D) ²⁵ : +11.0° (C=1.0, MeOH)

IR (Neat): 3600-3300, 1680-1580, 1274, 1124, 900, 700 cm⁻¹

NMR (DMSO-d₆, δ): 1.86 (3H, d, J=6.0 Hz); 2.52-5.05 (9H, m); 6.40-8.00(9H, m); 8.10-8.20 (1H, m)

MASS: 485 (M+1), 417

9) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-butyrylpiperazine

α!_(D) ²⁴ : +15.1° (C=1.0, MeOH)

IR (Neat): 3650-3300, 1635, 1274, 1125, 1005, 900, 698 cm⁻¹

NMR (DMSO-d₆, δ): 0.86-0.97 (3H, m); 1.55 (2H, q, J=7.2 Hz); 2.29-5.10(11H, m); 6.90-7.00 (1H, m); 7.15-7.80 (6H, m); 8.12-8.18 (1H, m)

MASS: 487 (M+1), 417

10) (2R)-4-Acetyl-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)piperazine

α!_(D) ²⁴ : -12.1° (C=0.9, MeOH)

IR (Neat): 1650, 1630, 1450, 1350, 1320, 1270 cm⁻¹

NMR (CDCl₃, δ): 2.12 (3H, s); 2.25 (6H, s); 2.2-2.4 (2H, m); 2.6-3.5(5H, m); 3.6-3.8 (1H, m); 4.6-4.8 (1H, m); 6.6-7.4 (4H, m); 7.8-8.0 (2H,m)

MASS: 487 (M+1), 445

11) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(trans-cinnamaoyl)piperazine

mp: 87°-91° C.

α!_(D) ²⁴ : -3.0° (C=0.8, MeOH)

IR (Nujol): 1635, 1605, 1430 cm⁻¹

NMR (CDCl₃, δ): 2.0-2.3 (6H, m); 2.6-3.5 (5H, m); 3.6-4.5 (2H, m);4.6-5.4 (2H, m); 6.6-7.7 (11H, m); 7.78 (1H, d, J=15.2 Hz); 7.90 (1H, brs)

MASS: 575 (M+1), 445

12) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-propionylpiperazine

mp: 177°-178° C.

α!_(D) ²² : -8.7° (C=1.0, MeOH)

IR (Nujol): 3300, 1635, 1282, 1224, 1124, 905, 748 cm⁻¹

NMR (DMSO-d₆, δ): 0.90-1.15 (3H, m); 2.20-5.15 (11H, m); 6.75-8.25 (8H,m); 10.87 (1H, s)

MASS: 512 (M+1)

13) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-mesylpiperazine

mp: >225° C.

α!_(D) ²¹ : +20.6° (C=1.0, DMF)

IR (Nujol): 3390, 1634, 1318, 1280, 1139, 964, 898, 747 cm⁻¹

NMR (DMSO-d₆, δ): 2.80-5.10 (12H, m); 6.55-8.25 (8H, m); 10.91 (1H, s)

MASS: 534 (M+1), 456

Example 20 ##STR35##

To a stirred mixture of (2R)-1-3,5-bis(trifluoro-methyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine(0.15 g) and potassium carbonate (0.14 g) in dimethylformamide (10 ml)was added acetyl chloride (0.04 ml) at room temperature. After beingstirred for 3 hours, the reaction mixture was quenched with water (50ml) and extracted with dichloromethane (50 ml). The organic layer waswashed with aqueous sodium bicarbonate solution and brine, and driedover magnesium sulfate. After evaporation of the solvent, the residuewas purified on a silica gel column (10 g) eluting with a mixture ofdichloromethane and methanol (20:1). The fractions containing objectcompound were collected and evaporated under reduced pressure. To theresulting oily product was added a mixed solvent of ethyl ether anddiisopropyl ether, and the mixture was concentrated under reducedpressure. The obtained powder was collected by filtration and dried invacuo to give (2R)-4-acetyl-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl) piperazine(0.09 g) as a powder.

IR (CHCl₃): 3270, 2990, 2900, 1630 cm⁻¹

NMR (DMSO-d₆, δ): 1.9-2.2 (3H, m); 2.73 (1H, s); 2.89 (1H, s); 2.65-3.12(3H, m); 3.15-3.48 (1H, m), 3.65-4.10 (2H, m); 4.20-4.68 (1H, m);6.58-7.48 (5H, m); 7.60-8.26 (3H, m); 10.88 (1H, s)

MASS: 498 (M+1)

Example 21

The following compounds were obtained according to a similar manner tothat of Example 20.

1) (2R)-4-Acetyl-1-3,5-bis(trifluoromethyl)benzoyl!-2-(N-methyl-1H-indol-3-yl-methyl)piperazine

IR (CHCl₃): 3460, 3000, 2920, 1620 cm⁻¹

NMR (DMSO-d₆, δ): 1.9-2.2 (3H, m); 2.73 (1H, s); 2.89 (1H, s); 2.68-3.14(2H, m); 2.68-3.56 (2H, m); 3.71-3.75 (3H, s); 3.60-4.10 (2H, m);4.10-4.65 (1H, m); 6.60-8.28 (8H, m)

MASS: 512 (M+1)

2) (2R)-4- 3- 2-(Acetylamino)thiazol-4-yl!-trans-acryloyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)piperazine

mp: 145°-149° C.

α!_(D) ²¹ : -0.7° (C=1.0, MeOH)

IR (Nujol): 3200, 1690, 1635, 1605, 1545, 1500, 1350, 1340, 1320 cm⁻¹

NMR (CDCl₃, δ): 2.14 and 2.20 (6H, 2 s); 2.28 (3H, s); 2.6-5.3 (9H, m);6.5°-7.4 (6H, m); 7.10 (1H, m); 7.66 (1H, d, J=14.8 Hz); 7.86 (1H, brs); 9.2-9.7 (1H, m)

MASS: 639 (M+1), 445

3) (2R)-4- 3- 2-(Acetylamino)thiazol-4-yl!-trans-acryloyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

mp: 167°-172° C.

α!_(D) ²⁰ : -45.1° (C=1.0, MeOH)

IR (Nujol): 3550-3100, 1685, 1635, 1545, 1276, 1175, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.16 (3H, s); 2.75-5.15 (9H, m); 6.60-8.25 (11H, m);10.88 (1H, s); 12.20-12.45 (1H, m)

MASS: 650 (M+1)

Example 22

To a mixture of (2R)-2-benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!piperazine (0.3 g) and acetic acid (1.2 ml) indioxane (1.2 ml) was added 37% formalin (0.05 ml) at room temperature.The resulting mixture was cooled to 0° C., and then a solution of indole(0.08 g) in dioxane (1.2 ml) was added. The mixture was stirred at roomtemperature for 30 minutes and then quenched with water (6 ml). The pHof the resulting mixture was adjusted to 8.0 by addition of aqueoussodium bicarbonate solution. The mixture was extracted with ethylacetate and the extract was washed with brine, and dried over magnesiumsulfate. After evaporation of the solvent, the residue was purified or asilica gel column (15 g) eluting with a mixture of toluene and ethylacetate (5:1). The eluate was concentrated and treated with 4N hydrogenchloride in ethyl acetate solution to give (2R)-2-benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(1H-indol-3-yl-methyl)piperazinehydrochloride (0.31 g) as a powder like a foam.

mp: 168°-170° C.

α!_(D) ²⁸ : +0.7° (C=1.0, MeOH)

IR (Nujol): 3200, 2520, 1639, 1275, 1126, 903 cm⁻¹

NMR (DMSO-d₆, δ): 2.80-5.10 (11H, m); 6.84-6.87 (1H, m); 7.05-7.90 (11H,m); 8.16-8.20 (1H, m); 11.00-11.40 (1H, m); 11.57 (1H, s)

MASS: 546 (M+l) (free), 417, 130

Example 23

To a solution of (2R)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)piperazine(0.1 g) in dichloromethane (10 ml) was added 4N hydrogen chloride indioxane solution (0.05 ml) at 0° C. The resulting mixture was stirred atthe same temperature for 50 minutes and then concentrated under reducedpressure. The obtained powder was collected by filtration and washedwith ethyl ether to give (2R)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride (0.1 g).

IR (Nujol): 3340, 1648 cm⁻¹

NMR (DMSO-d₆, δ): 2.9-3.9 (8H, m); 3.9-5.2 (1H, m); 6.57-7.50 (5H, m);7.50-8.30 (3H, m); 9.40-10.00 (2H, m); 10.96 (1H, s)

MASS: 456 (M+1) (free)

Example 24

The following compounds were obtained according to a similar manner tothat of Example 23.

1) (2R)-4-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

NMR (DMSO-d₆, δ): 2.80-4.30 (9H, m); 4.40-4.75 and 4.95-5.15 (2H, 2 m);6.45-8.30 (13H, m); 10.85 (1H, s); 11.10-11.65 (1H, m)

2) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(3-phenylpropyl)piperazinehydrochloride

IR (Nujol): 3200, 1636 cm⁻¹

NMR (DMSO-d₆, δ): 2.00-2.25 (2H, m); 2.55-2.77 (2H, m); 2.90-4.16 (11H,m); 6.80-7.48 (10H, m); 7.55-8.28 (3H, m); 10.94 (1H, s); 11.26, 11.40(1H, br s)

MASS: 574 (M+1) (free)

3) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(N-methyl-1H-indol-3-yl-methyl)-4-methylpiperazinehydrochloride

mp: 221°-226° C.

IR (Nujol): 3340, 2700, 1624 cm⁻¹

NMR (DMSO-d₆, δ): 2.78 and 2.82 (3H, 2 s); 2.97-3.83 and 4.00-4.18 (8H,2 s); 3.71, 3.76 (3H, s); 4.48-4.69 and 4.98-5.16 (1H, 2 m); 6.62-8.29(8H, m); 11.36, 11.49 (1H, br s)

MASS: 484 (M+1) (free)

4) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-2-(N,N-dimethylamino)acetyl!-piperazine hydrochloride

IR (Nujol): 3300-3200, 2700, 1625 cm⁻¹

NMR (DMSO-d₆, δ): 2.5-2.8 (6H, m); 2.84-4.46 (11H, m); 6.50-8.29 (8H,m); 8.41 and 8.80 (1H, 2 br s); 11.00 (1H, s)

MASS: 541 (M+1) (free)

5) (2R)-4-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-2-(N-methyl-1H-indol-3-yl-methyl)piperazinehydrochloride

α!_(D) ²⁸ : +13.1° (C=1.0, CHCl₃)

IR (Nujol): 3360, 2550, 1636 cm⁻¹

NMR (DMSO-d₆, δ): 2.90-3.52 (4H, m); 3.59 and 3.64 (3H, 2 s); 3.52-4.29(5H, m); 4.47-4.74 and 4.90-5.10 (2H, 2 m); 6.50-8.30 (13H, m)

MASS: 560 (M+1) (free)

6) (2R)-2-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4-(methoxycarbonylmethyl) piperazinehydrochloride

mp: 126°-129° C.

α!_(D) ²⁵ : -12.1° (C=1.0, MeOH)

IR (Nujol): 3650, 3100, 2700-2100, 1745, 1635, 1277, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.80-5.20 (14H, m); 6.91-7.80 (7H, m); 8.19-8.23 (1H,m)

MASS: 489 (M+1) (free), 417

7) (2R)-4-Benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)piperazinehydrochloride

mp: 146°-150° C.

α!_(D) ²⁸ : -17.1° (C=1.0, MeOH)

IR (Nujol): 3350, 2700-2300 (br), 1640 cm⁻¹

NMR (DMSO-d₆, δ): 2.0-2.2 (6H, m); 2.8-4.3 (9H, m); 4.4-5.0 (2H, m);6.5-7.1 (3H, m); 7.4-7.8 (7H, m); 8.1-8.2 (1H, m)

MASS: 535 (M+1) (free)

8) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)piperazine hydrochloride

mp: 125°-130° C.

α!_(D) ²⁸ : -30.4° (C=1.0, MeOH)

IR (Nujol): 3350, 2700-2500 (br), 1640, 1500, 1360, 1330 cm⁻¹

NMR (DMSO-d₆, δ): 2.0-2.2 (6H, m); 2.6-5.0 (9H, m); 6.6-7.7 (5H, m);8.1-8.2 (1H, m); 9.2-9.6 (1H, br m)

MASS: 445 (M+1) (free)

9) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(3-phenylpropyl)piperazinehydrochloride

mp: 211°-212° C.

α!_(D) ²⁷ : -16.6° (C=1.0, MeOH)

IR (Nujol): 3350, 2700-2400 (br), 1630, 1500, 1360 cm⁻¹

NMR (DMSO-d₆, δ): 2.0-2.3 (8H, m); 2.6-4.0 (12H, m); 4.5-5.2 (1H, m);6.7-7.7 (10H, m); 8.1-8.2 (1H, m); 11.0-11.4 (1H, m)

MASS: 563 (M+1) (free)

10) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(methoxycarbonylmethyl)piperazinehydrochloride

mp: 167°-169° C.

α!_(D) ²⁵ : -30.0° (C=1.0, MeOH)

IR (Nujol): 3700-3100, 2750-2000, 1749, 1638, 1278, 1175, 1130, 903 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.15 (14H, m); 6.60-8.30 (8H, m); 10.97 (1H, s)

MASS: 528 (M+1) (free)

11) (2R)-2,4-Dibenzyl-1- 3,5-bis(trifluoromethyl)-benzoyl!piperazinehydrochloride

mp: 213°-217° C.

α!_(D) ²⁸ : -3.6° (C=1.0, MeOH)

IR (Nujol): 2700-2000, 1640, 1272, 1135 cm⁻¹

NMR (DMSO-d₆, δ): 2.90-4.30 (8H, m); 4.40-5.10 (3H, m); 6.80-7.60 (9H,m); 7.70-8.30 (4H, m); 11.30-11.80 (1H, m)

MASS: : 507 (M+1) (free), 417

12) (2R)-2-Benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-piperazinehydrochloride

mp: 222°-224° C.

α!_(D) ²⁸ : -7.4° (C=1.0, MeOH)

IR (Nujol): 3520, 2800-2300, 1640, 1272, 1980, 1130 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.20 (10H, m); 6.80-7.80 (7H, m); 8.15 (1H, s);9.66 (1H, br s)

MASS: 417 (M+1) (free)

13) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-3-(3-pyridyl)-trans-acryloyl!-piperazine hydrochloride

mp: 100°-110° C. (dec.)

α!_(D) ²⁴ : -2.5° (C=1.0, MeOH)

IR (Nujol): 3350, 2700-2500, 1640-1600, 1550, 1350, 1320 cm⁻¹

NMR (DMSO-d₆, δ): 2.0-2.3 (8H, m); 2.5-3.9 (5H, m); 4.3-5.1 (2H, m);5.0-6.0 (1H, br s); 6.2-7.2 (3H, m); 7.4-8.3 (6H, m); 8.8-9.0 (2H, m);9.2-9.4 (1H, m)

MASS: 576 (M+1) (free)

14) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(methoxycarbonylmethyl)piperazinehydrochloride

mp: 137°-1380C.

α!_(D) ²³ : -27.3° (C=1.0, MeOH)

IR (Nujol): 3340, 2700-2300, 1750, 1635, 1500, 1360 cm⁻¹

NMR (DMSO-d₆, δ): 2.0-2.3 (6H, m); 2.7-5.1 (11H, m); 3.74 (3H, m); 6.70(1H, br s); 6.9-7.2 (2H, m); 7.44 (1H, br s); 7.18 (1H, br s); 8.19 (1H,br s)

MASS: 517 (M+1) (free), 445

Example 25

The following compounds were obtained according to a similar manner tothat of Example 9.

1) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-4-(carbamoylmethyl)-2-(3,4-dimethylbenzyl)piperazinehydrochloride

mp: 185°-186° C.

α!_(D) ²³ : -22.8° (C=1.0, MeOH)

IR (Nujol): 3350, 3150, 1685, 1635, 1500, 1380, 1350, 1320 cm⁻¹

NMR (DMSO-d₆, δ): 2.0-2.3 (6H, m); 2.6-4.2 (13H, m); 4.5-5.2 (1H, m);6.6-8.3 (6H, m)

MASS: 502 (M+1) (free), 445

2) (² R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(carbamoylmethyl)piperazine

mp: 170°-173° C.

α!_(D) ²⁰ : -5.5° (C=1.0, MeOH)

IR (Nujol): 3550-3000, 1691, 1600, 1276, 1222, 1190, 1130, 902 cm⁻¹

NMR (DMSO-d₆, δ): 2.00-4.95 (11H, m), 6.60-8.25 (10H, m); 10.86 (1H, s)

MASS: 513 (M+1), 456

Example 26

A mixture of (2R)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)-4-(methoxycarbonyl-methyl)piperazine(0.15 g) and 30% methylamine ethanol solution (5 ml) was left at about4° C. in a refrigerator. After 24 hours, the mixture was evaporated andthe residue was chromatographed on a column of silica gel with a mixtureof dichloromethane and methanol. The eluates were collected andevaporated. The product was dissolved in ethyl acetate (2 ml) and thentreated with 4N hydrogen chloride in ethyl acetate solution to afford(2R)-1- 3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(N-methylcarbamoylmethyl)piperazinehydrochloride (0.14 g) as a white powder.

mp: 175°-1800C.

α!_(D) ²¹ : -26.0° (C=1.0, MeOH)

IR (Nujol): 3700-3100, 2700-2000, 1673, 1635, 1276, 1173, 1131, 903 cm⁻¹

NMR (DMSO-d₆, δ): 2.69 (3H, s); 2.80-5.10 (11H, m); 6.60-8.80 (9H, m);10.99 (1H, s)

MASS: 527 (M+1) (free)

Example 27

To a stirred mixture of (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(carboxymethyl)piperazinehydrochloride (210 mg), N-methylbenzylamine (52 mg) and triethylamine(0.19 ml) in dichloromethane (5 ml) was added2-chloro-1-methylpyridinium iodide (110 mg) under nitrogen atmosphere atroom temperature. The mixture was stirred at the same temperature for 1hour. After removal of the solvent, the residue was purified by columnchromatography on a silica gel eluting with a mixture of dichloromethaneand methanol (10:1). The eluate was concentrated and treated with 4Nhydrogen chloride in ethyl acetate solution to give (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(N-methyl-N-benzylcarbamoyl)methyl!-piperazine hydrochloride (190 mg) asa powder.

mp: 145°-149° C. (dec.)

α!_(D) ²¹ : -15.2° (C=0.5, MeOH)

IR (Nujol): 2700-2500, 1650, 1360, 1330 cm⁻¹

NMR (DMSO-d₆, δ): 2.10 and 2.18 (6H, 2 s); 2.86 and 2.95 (3H, 2 s);2.7-5.2 (13H, m); 6.6-6.8 (1H, m); 6.9-7.5 (8H, m); 7.67 (1H, br s);8.2-8.3 (1H, m); 10.0-10.4 (1H, m)

MASS: 606 (M+1) (free), 445

Example 28

A mixture of (2R)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(3,4-dimethylbenzyl)piperazine (0.5g), tert-butyl bromoacetate (0.2 ml) and triethylamine (0.31 ml) intetrahydrofuran (10 ml) was stirred at room temperature for 12 hours.After filtration, the filtrate was concentrated to a syrup, which wassubjected to a chromatography on a silica gel with a mixture of tolueneand ethyl acetate (20:1) to afford (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(tert-butoxycarbonylmethyl)piperazine (0.52 g). This compound was treated with 4N hydrogen chloridein ethyl acetate solution to give (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-4-carboxymethyl-2-(3,4-dimethylbenzyl)piperazinehydrochloride (0.33 g) as a white powder.

mp: 195°-197° C.

α!_(D) ²⁴ : -28.3° C. (C=1.0, MeOH)

IR (Nujol): 3100, 2700-2300, 1720, 1635, 1500, 1400 cm⁻¹

NMR (DMSO-d₆, δ): 2.10 and 2.18 (6H, 2 s); 2.7-5.2 (13H, m); 6.6-7.2(3H, m); 7.4-7.8 (2H, m); 8.20 (1H, br s)

MASS: 503 (M+1) (free)

Example 29

The following compounds were obtained according to a similar manner tothat of Example 6.

1) (2R)-1-(3,5-Dimethylbenzoyl)-2-(3,4-dimethylbenzyl)piperazine

IR (Neat): 3300, 3050-2700, 1620, 1500, 1420 cm⁻¹

NMR (CDCl₃, δ): 2.1-2.4 (12H, m); 2.6-5.1 (10H, m); 6.5-6.8 (3H, m);6.9-7.1 (3H, m)

MASS: 337 (M+1)

2) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1R)-1-(N-methyl-1H-indol-3-yl)ethyl!piperazine

IR (Neat): 3300, 1730, 1630, 1430 cm⁻¹

NMR (CDCl₃, δ): 1.4-1.5 (3H, m); 2.5-3.6 (7H, m); 3.70 (3H, s); 3.9-4.1(1H, m); 4.9-5.0 (1H, m); 6.6-7.4 (5H, m); 7.6-8.5 (3H, m)

MASS: 484 (M+1)

Example 30

The following compounds were obtained according to a similar manner tothat of Example 11.

1) (2R)-4-(Benzyloxycarbonylmethyl)-1- 3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)piperazine

IR (Neat): 3000-2700 (br), 1740, 1635, 1500, 1430 cm⁻¹

NMR (CDCl₃, δ): 2.1-2.3 (6H,.m); 2.4-3.8 (10H, m); 4.6-5.1 (1H, m); 5.17(2H, s); 6.65 (1H, br s); 6.9-7.5 (9H, m); 7.82 (1H, s)

MASS: 593 (M+1), 445

2) (2R)-1-(3,5-Dimethylbenzoyl)-2-(3,4-dimethylbenzyl)-4-(methoxycarbonylmethyl)piperazine

IR (Neat): 3000-2700, 1745, 1630, 1600, 1500, 1420 cm⁻¹

NMR (CDCl₃, δ): 2.1-2.4 (12H, m); 2.6-5.1 (11H, m); 3.72 (3H, s);6.4-6.9 (3H, m); 7.0-7.3 (3H, m)

MASS: 409 (M+1), 365

3) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4-trityl-1-piperazinyl)-carbonylmethyl!piperazine

mp: 160° 166° C.

α!_(D) ²¹ : -23.0° (C=0.5, DMF)

IR (Nujol): 3600-3100, 1635, 1277, 1175, 1133, 900 cm⁻¹

NMR (DMSO-d₆, o): 1.80-5.00 (19H, m); 6.60-8.20 (23H, m); 10.85 (1H, s)

MASS: 824 (M+1), 580

4) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(3-phthalimidopropyl)piperazine

mp: 146°-147° C.

α!_(D) ¹⁸ : -25.8° (C=0.5, MeOH)

IR (Nujol): 1765, 1700, 1630, 1610, 1500, 1450, 1420, 1390, 1350 cm⁻¹

NMR (CDCl₃, δ): 1.85 (2H, sext, J=9.0 Hz); 2.15 and 2.21 (6H, 2 s); 2.44(2H, t, J=9.0 Hz); 3.84 (2H, t, J=9.0 Hz); 2.6-5.2 (9H, m); 6.5-7.5 (4H,m); 7.7-8.0 (6H, m)

MASS: 632 (M+1)

5) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(3-pyridyl)carbonylmethyl!-piperazine hydrochloride

mp: 145°-155° C. (dec.)

α!_(D) ¹⁸ : -18.3° (C=1.0, MeOH)

IR (Nujol): 3350, 2700-2300, 1715, 1640, 1500, 1450, 1350 cm⁻¹

NMR (DMSO-d₆, δ): 2.1-2.4 (6H, m); 2.8-5.4 (12H, m); 6.7-7.4 (3H, m);7.47 (1H, br s); 7.7-8.6 (4H, m); 8.9-9.0 (1H, m); 9.24 (1H, br s)

MASS: 564 (M+1) (free), 445

6) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(2-phthalimidoethyl)piperazine

mp: 161°-162° C.

α!_(D) ²⁰ : +1.6° (C=0.5, DMF)

IR (Nujol): 1770, 1710, 1630, 1500, 1550, 1535, 1410, 1400, 1350 cm⁻¹

NMR (DMSO-d₆, δ) 2.02 and 2.12 (6H, 2 s); 2.2-4.8 (13H, m); 6.3-7.3 (3H,m); 7.41 (1H, s); 7.66 (1H, s); 7.8-8.0 (4H, m); 8.11 (1H, br s)

MASS: 618 (M+1)

7) (2R)-4- 4-(Ethoxycarbonyl)butyl!-1- 3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

α!_(D) ²⁰ : -0.6° (C=0.5, DMF)

IR (Neat): 3300, 1720, 1620, 1275, 1175, 1125, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.18 (3H, t, J=7.1 Hz); 1.30-5.00 (19H, m); 6.60-8.20(8H, m); 10.85 (1H, s)

MASS: 584 (M+1), 456

8) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-3-(methoxycarbonyl)propyl!piperazine hydrochloride

mp: 133°-134° C.

α!_(D) ¹⁸ : +0.8° (C=0.5, DMF)

IR (Nujol): 3600-3100, 2800-2000, 1725, 1635, 1277, 1173, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.90-5.20 (18H, m); 6.60-8.20 (8H, m); 10.94 (1H, s);11.10-11.50 (1H, m)

MASS: 556 (M+l) (free)

9) (2R)-4- 3-(Benzyloxycarbonyl)propyl!-1- 3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

α!_(D) ²¹ : 1.8° (C=0.5, DMF)

IR (Neat): 3550-3100, 1727, 1625, 1274, 1130, 900 cm⁻¹

NMR (DMSO-d₆, 6): 1.70-2.40 (6H, m); 2.60-5.00 (9H, m); 5.12 (2H, s);6.60-8.20 (13H, m); 10.85 (1H, s)

MASS: 632 (M+1)

10) (2R)-4-(Benzyloxycarbonylmethyl)-1- 3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

α!_(D) ²¹ : -11.6° (C=1.0, MeOH)

IR (Neat): 3600-3100, 1735, 1626, 1275, 1129, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.20-5.20 (13H, m); 6.60-8.20 (13H, m); 10.85 (1H, brs)

MASS: 604 (M+1), 454

11)(2R)-4-(Benzyloxycarbonylmethyl)-2-(1H-indol-3-yl-methyl)-1-(3,5-dimethylbenzoyl)piperazine

mp: 148°-150° C.

α!_(D) ²¹ : +40.2° (C=0.5, DMF)

IR (Nujol): 3200, 1735, 1604, 1149, 734 cm⁻¹

NMR (DMSO-d₆, δ): 2.10-4.40 (17H, m); 5.13 (2H, s); 6.50-7.80 (13H, m);10.85 (1H, s)

MASS: 496 (M+1)

12) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-4-(4-fluorophenyl)carbonylmethyl!-2-(1H-indol-3-yl-methyl)piperazine

mp: 95°-105° C.

α!_(D) ¹⁷ : -21.2° (C=0.5, MeOH)

IR (Nujol): 3450-3100, 1628, 1595, 1277, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.20-4.95 (11H, m); 6.50-8.20 (12H, m); 10.81 (1H, s)

MASS: 592 (M+1)

13) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-4-(methoxycarbonyl)benzyl!piperazine

mp: 75°-78° C.

α!_(D) ²¹ : -40.8° (C=0.5, MeOH)

IR (Nujol): 3450-3100, 1716, 1625, 1277, 1170, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.00-5.00 (14H, m); 6.60-8.20 (12H, m); 10.79 (1H, s)

MASS: 604 (M+1)

14) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4-nitrobenzyl)piperazine

α!_(D) ²¹ : -55.0° (C=0.5, DMF)

IR (Neat): 3300, 1625, 1516, 1340, 1275, 1170, 1128, 902 cm⁻¹

NMR (DMSO-d₆, δ) 2.00-5.00 (11H, m); 6.55-8.30 (12H, m); 10.79 (1H, s)

MASS: 591 (M+1), 456

15) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-4-(N,N-dimethylcarbamoyl)-benzyl!piperazine hydrochloride

mp: 143°-155° C.

α!_(D) ²¹ : -24.2° C. (C=0.5, DMF)

IR (Nujol): 3600-3100, 2750-2000, 1610, 1277, 1170, 1128, 900 cm⁻¹

NMR (DMSO-d₆, δ) 2.80-5.20 (17H, m); 6.50-8.25 (12H, m); 10.81 (1H, s);11.40-11.80 (1H, m)

MASS: 617 (M+1) (free), 456

Example 31

The following compounds were obtained according to a similar manner tothat of Example 16.

1) (2R)-4-(4-Amino-trans-cinnamoyl)-1- 3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

mp: 147°-155° C.

α!_(D) ²² : -24.8° (C=1.0, MeOH)

IR (Nujol): 3600-3100, 2630-2100, 1635, 1510, 1277, 1175, 1130, 902 cm⁻¹

NMR (DMSO-d₆, δ) 2.75-5.20 (9H, m); 6.17-8.22 (16H, m); 10.90-11.10 (1H,m)

MASS: 601 (M+1) (free)

2) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(4-methoxy-trans-cinnamoyl)piperazine

mp: 67°-76° C.

α!_(D) ²¹ : -9.4° (C=1.0, MeOH)

IR (Nujol): 1645, 1600, 1575, 1510, 1540, 1350, 1320 cm⁻¹

NMR (CDCl₃, δ): 2.14 and 2.22 (6H, 2 s); 2.6-5.3 (9H, m); 3.85 (3H, s);6.5-7.7 (10H, m); 7.75 (1H, d, J=15.1 Hz); 7.89 (1H, br s)

MASS: 605 (M+l)

3) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-3-(2-thienyl)-trans-acryloyl!piperazine

mp: 78°-80° C.

α!_(D) ²¹ :+1.70 (C=1.0, MeOH)

IR (Nujol): 1635, 1600, 1500, 1350, 1330 cm⁻¹

NMR (CDCl₃, δ): 2.15 and 2.21 (6H, 2 s); 2.6-5.3 (9H, m); 6.4-7.7 (9H,m); 7.8-8.0 (2H, m)

MASS: 581 (M+1), 445

4) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(2-pyrazinyl)carbonyl!piperazine dihydrochloride

mp: 92°-95° C.

α!_(D) ²² : -2.60 (C=0.5, MeOH)

IR (Nujol): 3600-3100, 2750-2000, 1630, 1276, 1174, 1128, 900 cm⁻¹

NMR (DMSO-d₆, a) 2.80-5.20 (9H, m); 6.15-9.05 (11H, m); 10.78-10.92 (1H,m)

MASS: 562 (M+1) (free), 456

5) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-4-(dimethylamino)benzoyl!piperazine

IR (CHC1₃): 3250, 2990, 2900, 1602, 1522 cm⁻¹

NMR (DMSO-d₆, δ): 2.97 (6H, s); 2.58-3.60 (6H, m); 3.82-4.96 (3H, m);6.54-8.26 (12H, m); 10.84 (1H, s)

MASS: 603 (M+1)

6) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4-hydroxybenzoyl)piperazine

mp: >145° C.

IR (Nujol): 3330, 1638, 1600 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-3.67 (6H, m); 3.82-4.99 (3H, m); 6.50-8.24 (12H,m); 9.90 (1H, s); 10.84 (1H, s)

MASS: 576 (M+1)

7) (2R)-4-(4-Acetoxybenzoyl)-1- 3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

mp: 196°-197° C.

IR (Nujol): 3400, 1733, 1625 cm⁻¹

NMR (DMSO-d₆, a): 2.30 (3H, s); 3.00-5.05 (9H, m); 6.52-8.28 (12H, m);10.83 (1H, s)

MASS: 618 (M+1)

8) (2R)-4-(4-Cyanobenzoyl)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

mp: 205°-207° C.

IR (Nujol): 3260, 2220, 1626 cm⁻¹

NMR (DMSO-d₆, δ): 2.76-5.10 (9H, m); 6.44-8.25 (12H, m); 10.80 and 10.88(1H, 2 s)

MASS: 585 (M+1)

9) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4-acetylbenzoyl)piperazine

mp: 245°-248° C.

IR (Nujol): 3270, 1683, 1638, 1626, 1609 cm⁻¹

NMR (DMSO-d₆, a): 2.62 (3H, s); 2.80-5.08 (9H, m); 6.40-8.26 (12H, m);10.76 and 10.89 (1H, 2 s)

MASS: 602 (M+1)

10) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-3-(3-pyridyl)propionyl!piperazine

α!_(D) ¹⁸ : -3.5° (C=1.0, MeOH)

IR (Neat): 1635, 1570, 1500, 1460, 1430 cm⁻¹

NMR (CDCl₃, δ): 2.19 and 2.21 (6H, 2 s); 2.5-3.5 (10H, m); 3.7-5.3 (3H,m); 6.5-7.5 (6H, m); 7.5-7.7 (1H, m); 7.8-7.9 (1H, m); 8.4-8.6 (2H, m)

MASS: 578 (M+1)

11) (2R)-1-(3,5-Dimethylbenzoyl)-2-(3,4-dimethylbenzyl)-4-3-(3-pyridyl)-trans-acryloyl!piperazine

α!_(D) ¹⁸ : +4.9° (C=0.5, MeOH)

IR (Neat): 3100-2800 (br), 1620, 1500, 1460, 1420, 1360, 1280 cm⁻¹

NMR (CDCl₃, δ): 2.0-2.4 (12H, m); 2.7-5.2 (9H, m); 6.5-7.1 (7H, m);7.2-7.4 (1H, m); 7.6-7.9 (2H, m); 8.6-8.9 (2H, m)

MASS: 468 (M+1)

12) (² R)-4-Benzoyl-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

IR (Nujol): 3250, 1622 cm⁻¹

NMR (DMSO-d₆, δ) 2.80-5.05 (9H, m); 6.50-8.25 (13H, m); 10.84 (1H, s)

MASS: 560 (M+1)

13) (² R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4-nitrobenzoyl)piperazine

mp: 151°-153° C.

IR (Nujol): 3330, 1653, 1626, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 2.20-5.10 (9H, m); 6.40-8.40 (12H, m); 10.77 and 10.91(1H, 2 s)

MASS: 605 (M+1)

14) (2R)-4-(2-Chloroacetyl)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(3,4-dimethylbenzyl)piperazine

IR (Neat): 1645, 1500, 1430, 1370, 1355, 1340, 1320 cm⁻¹

15) (² R)-4-(trans-Cinnamoyl)-1- 3,5-bis(trifluoromethyl)-benzoyl!-2-(IR)-1-(N-methyl-1H-indol-3-yl)ethyl!-piperazine

mp: 90°-91° C.

α!_(D) ²⁴ : +0.6° (C=0.5, MeOH)

IR (Nujol): 1640, 1600, 1450, 1380, 1350 cm⁻¹

NMR (CDCl₃, δ): 1.4-1.7 (3H, m); 2.5-5.3 (8H, m); 3.69 (3H, s); 6.6-7.9(15H, m)

MASS: 614 (M+1)

16) (2R)-4-(trans-Cinnamoyl)-2-(3,4-dichlorobenzyl)-1-3,5-bis(trifluoromethyl)benzoyl!piperazine

mp: 83°-86° C.

α!_(D) ²⁴ : +8.2° (C=1.0, MeOH)

IR (Nujol): 1640, 1605, 1430, 1350, 1320 cm⁻¹

NMR (CDCl₃, δ): 2.8-3.2 (4H, m); 3.3-3.6 (3H, m); 3.8-5.2 (2H, m);6.6-7.7 (11H, m); 7.79 (1H, d, J=15.3 Hz); 7.95 (1H, br s)

MASS: 615 (M+1)

17) (2R)-4-(2,2,2-Trifluoroacetyl)-1- 3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine.

mp: 197.6°-198.8° C.

IR (Nujol): 3300, 1690, 1628, 1610 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.20 (9H, m); 6.50-8.25 (8H, m); 10.88 (1H, s)

MASS: 552 (M+1)

18) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-4-cyclohexylcarbonyl-2-(1H-indol-3-yl-methyl)piperazine

mp: 200°-201° C.

α!_(D) ²² : -3.8° (C=1.0, MeOH)

IR (Nujol): 3340, 1630, 1617, 1272, 1184, 1136, 902 cm⁻¹

NMR (DMSO-d₆, δ): 1.00-1.95 (10H, m); 2.40-5.20 (10H, m); 6.55-8.25 (8H,m); 10.80-11.00 (1H, m)

MASS: 566 (M+1)

19) (2R)-4-(2-Chloroacetyl)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

mp 185°-187° C.

α!_(D) ²² : -0.1° (C=1.0, MeOH)

IR (Nujol): 3280, 1660, 1630, 1279, 1225, 1190, 1125, 905, 750 cm⁻¹

NMR (DMSO-d₆, δ): 2.70-5.10 (11H, m); 6.55-8.20 (8H, m); 10.90 (1H, s)

MASS: 532 (M+1), 456

20) (2R)-4-(3,4-Difluoro-trans-cinnamoyl)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

mp: 214°-217° C.

α!_(D) ²¹ : -30.6° C. (C=1.0, MeOH)

IR (Nujol): 3270, 1625, 1607, 1511, 1276, 1131, 900 cm⁻¹

NMR (DMSO-d₆, δ) 2.70-5.20 (9H, m); 6.60-8.25 (13H, m); 10.85 (1H, br s)

MASS: 622 (M+1)

21) (2R)-4-(4-Acetylamino-trans-cinnamoyl)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

mp: 148°-154° C.

IR (Nujol): 3600-3100, 1637, 1590, 1278, 1175, 1133, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.06 (3H, s); 2.75-5.20 (9H, m); 6.60-8.25 (12H, m);10.10 (1H, s); 10.87 (1H, br s)

MASS: 643 (M+1)

Example 32

The following compounds were obtained according to a similar manner tothat of Example 27.

1) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-N-(l-pyrrolyl)carbamoylmethyl!-piperazine dihydrochloride

mp: 190°-195° C.

α!_(D) ²¹ : -18.6° (C=0.5, DMF)

IR (Nujol): 3630-3060, 2750-2100, 1700, 1635, 1278, 1175, 1131, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.70-5.20 (11H, m); 6.00-8.30 (13H, m); 10.95 (1H, s);11.00-12.10 (2H, m)

MASS: 578 (M+1) (free), 456

2) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-N-methyl-N-(2-dimethylaminoethyl)-carbamoylmethyl!piperazinedihydrochloride

mp: 200°-205° C.

α!_(D) ²² : -20.2° (C=0.5, DMF)

IR (Nujol): 3340, 3180, 2670, 1655, 1275, 1195, 1129, 908 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.10 (24H, m); 6.60-8.30 (8H, m); 10.00-10.90(2H, m); 11.00 (1H, s)

MASS: 598 (M+1) (free)

3) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-N-(2-piperidinoethyl)-carbamoylmethyl!piperazine dihydrochloride

mp: 194°-201° C.

α!_(D) ²² : -9.6° (C=0.5, DMF)

IR (Nujol): 3680-3100, 2750-1970, 1680, 1635, 1274, 1170, 1125, 902 cm⁻¹

NMR (DMSO-d₆, δ): 0.80-5.15 (25H, m); 6.80-8.25 (9H, m); 8.95-9.25 (1H,m); 10.40-10.60 (1H, br s); 11.00 (1H, s)

MASS: 624 (M+1) (free)

4) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-N- 2-(l-pyrrolidino)ethyl!-carbamoylmethyl!piperazine dihydrochloride

mp: 183°-190° C.

α!_(D) ²² : -9.4° (C=0.5, DMF)

IR (Nujol): 3700-3100, 2750-1955, 1683, 1635, 1273, 1170, 1123, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.80-5.10 (23H, m); 6.60-8.30 (9H, m); 8.90-9.15 (1H,m); 10.75-10.95 (1H, m);

10.98 (1H, s)

MASS: 610 (M+1) (free), 456

5) (2R)-4- N-(Benzyloxy)carbamoylmethyl-1- 3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine hydrochloride

mp: 161°-167° C.

α!_(D) ²⁴ : -16.6° (C=0.5, DMF)

IR (Nujol) 3600-3000, 2750-2000, 1685, 1635, 1277, 1173, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 3.00-5.20 (13H, m); 6.60-8.30 (14H, m); 11.01 (1H, s);11.60-12.05 (1H, m)

MASS: 619 (M+1) (free), 456

6) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-N-(3-pyridyl)carbamoylmethyl!-piperazine dihydrochloride

mp: 115°-122° C. (dec.)

α!_(D) ¹⁸ : -34.1° (C=0.5, MeOH)

IR (Neat): 3300, 3000-2400, 1635, 1560, 1430 cm⁻¹

NMR (DMSO-d₆, δ): 2.11 and 2.18 (6H, 2 s); 2.7-5.8 (13H, m); 6.5-7.8(5H, m); 7.94 (1H, dd, J=8.3 Hz and 5.2 Hz); 8.18 (1H, br s); 8.52 (1H,d, J=8.3 Hz); 8.61 (1H, d, J=5.2 Hz); 9.16 (1H, d, J=2.0 Hz); 12.1-12.4(1H, m)

MASS: 579 (M+1) (free)

7) (2R)-4-(Hydrazinocarbonylmethyl)-1- 3,⁵ -bis(trifluoromethyl)benzoyl!-2-(1H-indol-³ -yl-methyl)piperazine dihydrochloride

mp: 204°-209° C.

α!_(D) ²⁴ : -19.4° (C=0.5, DMF)

8) (2R)-4- N- 3-(Diethylamino)propyl!carbamoylmethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinedihydrochloride

mp: 159°-170° C.

α!_(D) ²⁶ : -6.2° (C=0.5, DMF)

IR (Nujol): 3650-3100, 2750-1950, 1635, 1276, 1171, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.15-1.30 (8H, m); 3.00-5.15 (19H, m); 6.60-8.30 (9H,m); 8.90-9.15 (1H, m); 10.40-10.70 (1H, m); 11.00-11.10 (1H, m)

MASS: 626 (M+1) (free)

9) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(N,N-dimethylcarbamoylmethyl)-piperazinehydrochloride

mp: 165° 168° C.

α!_(D) ²² : -29.0° (C =0.5, MeOH)

IR (Nujol): 3600-3100, 2700-2100, 1650, 1278, 1174, 1130, 902 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.15 (17H, m); 6.80-8.25 (8H, m); 10.10-10.40(1H, m); 11.01 (1H, s)

MASS: 541 (M+1) (free)

10) (2R)-4- 2-(N-Benzyl-N-methylamino)acetyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

mp: 157°-165° C.

α!_(D) ²² : -8.3° (C=1.0, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1635, 1277, 1175, 1130, 902 cm⁻¹

NMR (DMSO-d₆, δ): 2.70-5.20 (16H, m); 6.60-8.25 (13H, m); 10.00-10.25(1H, m); 10.97 (1H, br s)

MASS: 617 (M+1) (free), 456

11)(2R)-4-(Carbamoylmethyl)-1-(3,5-dimethylbenzoyl)-2-(3,4-dimethylbenzyl)piperazinehydrochloride

mp: 152-160° C. (dec.)

α!_(D) ¹⁸ : +3.1° (C=0.5, MeOH)

IR (Nujol): 3300 (br), 3150, 1685, 1625, 1595, 1500, 1510 cm⁻¹

NMR (DMSO-d₆, δ): 2.1-2.4 (12H, m); 2.7-5.2 (12H, m); 6.4-8.2 (8H, m)

MASS: 394 (M+1) (free), 337

12) (2R)-4-(3-Carbamoylpropyl)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

mp: 165°-170° C.

IR (Nujol): 3670-3050, 2750-2000, 1635, 1275, 1171, 1128, 903 cm⁻¹

NMR (DMSO-d₆, δ): 1.80-5.20 (15H, m); 6.60-8.30 (10H, m); 10.95 (1H, s);11.22 (1H, br s)

MASS: 541 (M+1) (free), 457

13 )(2R)-4-(Carbamoylmethyl)-1-(3,5-dimethylbenzoyl)-2-(1H-indol-3-yl-methyl)piperazine

mp: >225° C.

α!_(D) ²¹ : +41.0° (C=0.5,. DMF)

IR (Nujol): 3410, 3200, 1674, 1610, 1220, 750 cm⁻¹

NMR (DMSO-d₆, δ): 2.16 (6H, s); 2.50 (2H, s); 2.60-5.00 (9H, m);6.50-7.85 (10H, m); 10.81 (1H, s)

MASS: 405 (M+1)

14) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-N-(4-methyl-1-piperazinyl)carbamoyl-methyl!piperazine dihydrochloridepentahydrate

mp: 212°-216° C.

α!_(D) ²⁹ : -13.0° (C=0.5, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1685, 1632, 1276, 1176, 1131, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.40-5.10 (22H, m); 6.60-8.30 (9H, m); 9.62 (1H, S);10.20-10.60 (1H, m); 11.01 (1H, s); 11.00-11.30 (1H, m)

MASS: 611 (M+1) (free)

15) (2R)-4-N-(2-Diethylaminoethyl)carbamoylmethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinedihydrochloride

mp: 176°-179° C.

α!_(D) ¹⁹ : -8.4° (C=0.5, DMF)

IR (Nujol): 3650-3100, 2750-2000, 1681, 1635, 1275, 1173, 1130, 901 cm⁻¹

NMR (DMSO-d₆, δ): 1.20-1.30 (6H, m); 2.70-5.20 (19H, m); 6.60-8.30 (9H,m); 9.09 (1H, br s); 10.60 (1H, br s); 10.99 (1H, s)

MASS: 612 (M+1) (free)

16 ) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-N-(isopropyl)carbamoylmethyl!-piperazine

mp: 130°-1340C.

α!_(D) ¹⁸ : -12.6° (C=0.5, DMF)

IR (Nujol): 3500-3100, 1678, 1626, 1277, 1168, 1126, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.09 (6H, d, J=6.5 Hz); 2.10-5.00 (12H, m); 6.60-8.20(9H, m); 10.85 (1H, s)

MASS: 555 (M+1)

17) (2R)-4- N-(Benzyloxycarbonylmethyl)carbamoylmethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

mp: 90°-93° C.

α!_(D) ²⁰ : -13.6° (C=0.5, MeOH)

IR (Nujol): 3600-3100, 1739, 1662, 1628, 1510, 1277, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.20-5.20 (15H, m); 6.60-8.35 (14H, m); 10.84 (1H, s)

MASS: 661 (M+1)

18) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-N-(2-dimethylaminoethyl)-carbamoylmethyl!piperazine

mp: 123° 125° C.

α!_(D) ¹⁹ : -12.6° (C=0.5, MeOH)

IR (Nujol): 3400-3100, 1659, 1630, 1510, 1279, 1126, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.16 (6H, s); 2.30-5.00 (15H, m); 6.60-8.20 (9H, m);10.86 (1H, s)

MASS: 584 (M+1) 19) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-N-(3-pyridylmethyl)carbamoylmethyl!-piperazine

mp: 105°-109° C.

α!_(D) ¹⁹ : -26.5° (C=0.5, MeOH)

IR (Nujol): 3600-3100, 1628, 1510, 1275, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.10-5.00 (13H, m); 6.60-8.60 (13H, m); 10.84 (1H, s)

MASS: 604 (M+1)

20) (2R)-4- N-(4-Fluorobenzyl)carbamoylmethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

mp: 94°-97° C.

α!_(D) ²⁰ : -34.4° (C=0.5, MeOH)

IR (Nujol): 3600-3100, 1628, 1509, 1276, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.15-5.20 (13H, m); 6.60-8.50 (13H, m); 10.84 (1H, s)

MASS: 621 (M+1), 456

21) (2R)-4- N-(Cyclohexylmethyl)carbamoylmethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

mp: 100°-103° C.

α!_(D) ²¹ : -17.6° (C=0.5, MeOH)

IR (Nujol): 3500-3100, 1630, 1522, 1276, 1170, 1130, 898 cm⁻¹

NMR (DMSO-d₆, δ): 0.80-2.40 (13H, m); 2.60-5.20 (11H, m); 6.60-8.20 (9H,m); 10.86 (1H, s)

MASS: 609 (M+1), 456

22) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-N-(2-methoxyethyl)carbamoylmethyl!-piperazine hydrochloride

α!_(D) ²¹ : -7.2° (C=0.5, DMF)

IR (Nujol): 3700-3100, 2700-2000, 1720-1590, 1271, 1120, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.70-5.10 (18H, m); 6.60-8.90 (9H, m); 10.98 (1H, s)

MASS: 571 (M+1) (free)

23) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-4-N-(2-hydroxyethyl)carbamoylmethyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

mp: 150°-160° C.

IR (Nujol): 3600-3100, 2700-2100, 1670, 1635, 1276, 1173, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.70-5.10 (16H, m); 6.60-8.80 (9H, m); 10.97 (1H, s)

MASS: 557 (M+1) (free), 456

24) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-N-(dimethylamino)carbamoylmethyl!-piperazine

mp: 115°-125° C.

α!_(D) ¹⁷ : -5.0° (C=0.5, DMF)

IR (Nujol): 3600-3100, 1670, 1625, 1277, 1170, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.10-5.00 (17H, m); 6.60-8.75 (9H, m); 10.85 (1H, s)

MASS: 556 (M+1)

25) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-4-4-(2-hydroxyethyl)-1-piperazinyl!carbonylmethyl!-2-(1H-indol-3-yl-methyl)piperazinedihydrochloride

mp: 199°-208° C.

α!_(D) ¹⁹ : -25.4° (C=0.5, DMF)

IR (Nujol): 3650-3050, 2750-2000, 1645, 1275, 1173, 1128, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.90-5.20 (24H, m); 6.60-8.30 (8H, m); 10.30-10.80(1H, m); 11.00 (1H, s); 11.00-11.35 (1H, br s)

MASS: 626 (M+1) (free)

26) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-4-(2-pyridyl)-1-piperazinyl!-carbonylmethyl!piperazine trihydrochloride

mp: 190°-200° C.

IR (Nujol) 3650-3050, 2750-1980, 1635, 1272, 1170, 1122, 900 cm⁻¹

NMR (DMSO-d₆, δ): 3.00-5.20 (19H, m); 6.20-8.30 (12H, m); 11.02 (1H, s)

MASS: 659 (M+1) (free), 456

27) (2R)-4- (4-Acetyl-1-piperazinyl)carbonylmethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

mp: 180°-190° C.

α!_(D) ¹⁹ : -31.6° (C=0.5, DMF)

IR (Nujol): 3650-3100, 2750-2000, 1635, 1278, 1172, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.05 (3H, s); 3.00-5.20 (19H, m); 6.60-8.30 (8H, m);10.20-10.60 (1H, m); 11.01 (1H, s)

MASS: 624 (M+1) (free)

28) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4-phenyl-1-piperazinyl)-carbonylmethyl!piperazine dihydrochloride

mp: 190°-200° C.

α!_(D) ²² : -30.6° (C=0.5, DMF)

IR (Nujol): 3650-3100, 2750-2000, 1640, 1279, 1172, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.70-5.30 (19H, m); 6.60-8.30 (13H, m); 10.50-10.70(1H, m); 11.03 (1H, s)

MASS: 658 (M+1) (free)

29) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4,1'-bipiperidin-1-yl)carbonylmethyl!piperazine dihydrochloride

mp: 209°-220° C.

α!_(D) ²⁴ : -31.6° (C=0.5, DMF)

IR (Nujol): 3680-3050, 2750-1990, 1640, 1274, 1170, 1127, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.20-5.20 (30H, m); 6.60-8.25 (8H, m); 10.20-10.50(1H, m); 11.02 (2H, br s)

MASS: 664 (M+1) (free)

30) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4-cyclohexyl-1-piperazinyl)-carbonylmethyl!piperazine dihydrochloride

mp: 207°-220° C.

α!_(D) ²² : -24.0° (C=0.5, DMF)

IR (Nujol): 3650-3050, 2750-2000, 1650, 1278, 1172, 1131, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.00-5.10 (30H, m); 6.60-8.25 (8H, m); 10.40-10.80(1H, m); 10.99 (1H, s); 11.62 (1H, br s)

MASS: 664 (M+1) (free), 456 31) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4-propyl-1-piperazinyl)-carbonylmethyl!piperazine dihydrochloride

mp: 206°-214° C.

α!_(D) ²² : -25.4° (C=0.5, DMF)

IR (Nujol): 3650-3100, 2750-1980, 1640, 1278, 1173, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 0.92 (3H, t, J=7.2 Hz); 1.65-5.20 (23H, m); 6.60-8.25(8H, m); 10.99 (1H, s); 11.45-11.70 (1H, m)

MASS: 624 (M+1) (free)

32) (2R)-4- ((2S)-2-Carbamoyl-1-pyrrolidino)-carbonylmethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

mp: 196°-203° C.

α!_(D) ²⁴ : -50.6° (C=0.5, DMF)

IR (Nujol): 3600-3050, 2750-2000, 1650, 1277, 1171, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.80-5.20 (18H, m); 6.60-8.30 (10H, m); 10.20-11.00(1H, m); 11.02 (1H, s)

MASS: 610 (M+1) (free)

33) (2R)-4- (4-Acetylamino-4-phenylpiperidino)-carbonylmethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

mp: 210°-219° C.

α!_(D) ²⁴ : -25.0° (C=0.5, DMF)

IR (Nujol): 3600-3100, 2700-2000, 1645, 1278, 1173, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.60-5.15 (22H, m); 6.60-8.25 (14H, m); 10.00-10.30(1H, m); 11.01 (1H, s)

MASS: 714 (M+1) (free)

34) (2R)-4- (4-Ethoxycarbonylpiperidino)carbonylmethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

α!_(D) ²³ : -11.4° (C=0.5, DMF)

IR (Neat): 3260, 1724, 1630, 1276, 1174, 1128, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.18 (3H, t, J=7.1 Hz); 1.20-5.00 (22H, m); 6.60-8.20(8H, m); 10.87 (1H, s)

MASS: 653 (M+1)

35) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4-piperidon-1-yl)carbonylmethyl!-piperazine hydrochloride

mp: 160°-170° C.

α!_(D) ²⁶ : -28.6° (C=0.5, DMF)

IR (Nujol): 3600-3100, 2750-2000, 1710, 1650, 1278, 1175, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.30-5.20 (19H, m); 6.60-8.30 (8H, m); 10.20-10.60(1H, m); 11.02 (1H, s)

MASS: 595 (M+1) (free)

36) (2R)-4- (3-Carbamoylpiperidino)carbonylmethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

mp: 189°-196° C.

IR (Nujol): 3600-3100, 2750-2000, 1640, 1277, 1170, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.20-5.15 (20H, m); 6.60-8.30 (10H, m); 10.00-10.30(1H, br s); 11.00 (1H, s)

MASS: 624 (M+1) (free)

37) (2R)-4- (4-Acetylamino-4-phenylpiperidino)-carbonylmethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)piperazine

mp: 158°-165° C. (dec.)

α!_(D) ¹⁸ 8 : -14.6° (C=0.5, MeOH)

IR (Nujol): 3300, 1630, 1540, 1360 cm⁻¹

NMR (CDCl₃, δ): 2.02 (3H, s); 1.8-2.5 (11H, m); 2.6-5.2 (14H, m); 5.66(1H, br s); 6.5-6.7 (1H, m); 6.9-7.5 (9H, m); 7.82 (1H, br s)

FABMASS: 703 (M+1), 644, 457, 414

38) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(³,⁴-dimethylbenzyl)-4-(morpholinocarbonylmethyl)-piperazine hydrochloride

mp: 100°-125° C. (dec.)

α!_(D) ¹⁸ : -20.8° (C=0.5, MeOH)

IR (Nujol): 3300 (br), 2700-2500, 1650, 1450, 1360 cm⁻¹

NMR (DMSO-d₆, δ): 2.11 and 2.18 (6H, 2 s); 2.7-5.2 (19H, m); 6.6-7.3(3H, m); 7.3-7.8 (2H, m); 8.1-8.3 (1H, m); 10.0-10.4 (1H, br m)

MASS: 572 (M+1) (free), 445

39) (2R)-4- 2-(4-Acetylamino-4-phenylpiperidino)acetyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl) piperazine

mp: 120°-130° C. (dec.)

α!_(D) ¹⁸ : -7.4° (C=0.1, MeOH)

IR (Nujol): 3300, 1630, 1540, 1380, 1320, 1280 cm⁻¹

NMR (CDCl₃, δ): 2.01 (3H, s); 2.17 and 2.21 (6H, 2 s); 2.0-5.3 (19H, m);5.53 (1H, d, J=6.2 Hz); 6.6-7.5 (10H, m); 7.84 (1H, s)

FABMASS: 703 (M+1), 642, 514, 414

40) (2R)-4- (4-Carbamoylpiperidino)carbonylmethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

mp: 197°-208° C.

α!_(D) ²⁰ : -29.6° (C=0.5, DMF)

IR (Nujol): 3650-3050, 2750-2000, 1640, 1275, 1173, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.20-5.10 (20H, m); 6.60-8.25 (10H, m); 9.80-10.20(1H, m); 10.97 (1H, s)

MASS: 624 (M+1) (free)

41) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4-methyl-1-homopiperazinyl)-carbonymethyl!piperazine dihydrochloride

mp: 220°-225° C. (dec.)

α!_(D) ²¹ : -24.8° (C=0.5, DMF)

IR (Nujol): 3700-3100, 2750-1980, 1640, 1275, 1172, 1126, 903 cm⁻¹

NMR (DMSO-d₆, δ): 0.75-1.30 (2H, m); 2.00-5.20 (22H, m); 6.60-8.30 (8H,m); 10.50 (1H, br s); 11.01 (1H, s); 11.45 (1H, br s)

MASS: 610 (M+1) (free)

42) (2R)-4- (4-Ethyl-1-piperazinyl)carbonylmethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinedihydrochloride

mp: 205°-211° C.

α!_(D) ¹⁹ : -27.6° (C=0.5, DMF)

IR (Nujol): 3600-3100, 2700-2000, 1650, 1276, 1172, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.29 (3H, t, J=7.2 Hz); 2.80-5.20 (21H, m); 6.60-8.30(8H, m); 11.00 (1H, s); 11.60-11.80 (1H, m)

MASS: 610 (M+1) (free)

43) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(piperidinocarbonylmethyl)piperazinehydrochloride

mp: 180°-190° C.

α!_(D) ¹⁹ : -26.8° (C=0.5, DMF)

IR (Nujol): 3600-3100, 2700-2100, 1647, 1278, 1173, 1131, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.40-1.70 (6H, m); 3.10-5.20 (15H, m); 6.60-8.30 (8H,m); 10.00-10.40 (1H, m); 11.00 (1H, s)

MASS: 581 (M+1) (free)

44) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4-phenylpiperidino)carbonylmethyl!-piperazine hydrochloride

mp: 167°-173° C.

α!_(D) ¹⁹ : -30.8° (C=0.5, DMF)

IR (Nujol): 3600-3100, 2700-2000, 1640, 1276, 1172, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.20-5.20 (20H, m); 6.60-8.30 (13H, m); 10.00-10.40(1H, m); 11.00 (1H, s)

MASS: 657 (M+1) (free)

45) (2R)-4- (4-Benzylpiperidino)carbonylmethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

mp: 158°-160° C.

α!_(D) ¹⁹ : -27.2° (C=0.5, DMF)

IR (Nujol): 3600-3100, 2700-2000, 1640, 1276, 1174, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.00-5.20 (22H, m); 6.60-8.30 (13H, m); 9.90-10.40(1H, m); 10.99 (1H, s)

MASS: 671 (M+1) (free)

46) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(pyrrolidinocarbonylmethyl)piperazinehydrochloride

mp: 161°-166° C.

IR (Nujol): 3700-3100, 2700-2000, 1640, 1278, 1131, 902 cm⁻¹

NMR (DMSO-d₆, δ): 1.80-2.00 (4H, m); 3.00-5.20 (15H, m); 6.60-8.30 (8H,m); 11.00 (1H, s)

MASS: 567 (M+1) (free)

47) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4-methyl-1-piperazinyl)-carbonylmethyl!piperazine

mp: 105°-108° C.

α!_(D) ¹⁸ : -12.2° (C=0.5, DMF)

IR (Nujol): 3600-3100, 1630, 1275, 1165, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.10-5.00 (22H, m); 6.60-8.20 (8H, m); 10.87 (1H, s)

MASS: 596 (M+1)

48) (2R)-4-(4-Carbamoylbenzyl)-1- 3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

mp: 120°-126° C.

α!_(D) ²¹ : -37.6° (C=0.5, DMF)

IR (Nujol): 3600-3100, 1660, 1610, 1276, 1170, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.00-5.00 (11H, m); 6.50-8.30 (14H, m); 10.80 (1H, s)

MASS: 589 (M+1)

49) (2R)-4- N-(Carbamoylmethyl)carbamoylmethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

mp: 135°-145° C.

α!_(D) ²¹ : 15.0° (C=0.5, MeOH)

IR (Nujol): 3600-3100, 1730-1560, 1277, 1170, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.80-5.00 (13H, m); 6.60-8.20 (11H, m)

MASS: 570 (M+1), 456

50) (2R)-4-(4-Carbamoylbutyl)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

mp: 146°-156° C.

α!_(D) ²¹ : +0.4° (C=0.5, DMF)

IR (Nujol): 3650-3050, 2750-1900, 1635, 1275, 1175, 1125, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.40-5.20 (17H, m); 6.60-8.30 (10H, m); 10.95 (IH, s);11.05-11.40 (1H, m)

MASS: 555 (M+1) (free)

51) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-3- (4-methyl-1-homopiperazinyl)-carbonyl!propyl!piperazine

α!_(D) ²⁰ : -13.5° (C=1.0, MeOH)

IR (Neat): 3225, 1630, 1430, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 1.63-4.95 (28H, m); 6.60-8.19 (8H, m); 10.89 (1H s)

MASS: 638 (M+1)

52) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-3- N-(4-methyl-1-piperazinyl)carbamoyl!propyl!piperazine

α!_(D) ¹⁹ : -14.1 (C=1.0, MeOH)

IR (Neat): 3225, 1630, 1450, 1350, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 1.68-4.85 (23H, m); 2.15 (3H, s); 6.64-8.76 (9H, m);10.85 (1H, s)

MASS: 639 (M+1)

Example 33

The following compounds were obtained according to a similar manner tothat of Example 10.

1) (2R)-4-(4-Carboxybutyl)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

mp: 97°-100° C.

IR (Nujol): 3600-3100, 2700-2000, 1710, 1625, 1276, 1170, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.35-5.00 (17H, m); 6.60-8.20 (8H, m); 10.85 (1H, s);12.01 (1H, s)

MASS: 556 (M+1) (free)

2) (2R)-4-(4-Carboxybenzyl)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

mp: >210° C.

α!_(D) ²¹ : -36.4° (C=0.5, DMF)

NMR (DMSO-d₆, δ): 2.70-5.20 (l1H, m); 6.50-8.25 (12H, m); 10.86 (1H, s);11.30-13.40 (2H, m)

MASS: 590 (M+1) (free)

3) (2R)-4- (4-Carboxypiperidino)carbonylmethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

mp: 143°-150° C.

IR (Nujol) 3600-3100, 2750-2000, 1710, 1630, 1277, 1170, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.30-5.00 (20H, m); 6.60-8.20 (8H, m); 10.89 (1H, s);12.32 (1H, s)

MASS: 625 (M+1) (free)

Example 34

A mixture of (2R)-4- 3-(benzyloxycarbonyl)propyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine(0.15 g), 10% Pd charcoal (15 mg) and methanol (4.5 ml) was stirred for3 hours under hydrogen atmosphere (1 atm). The catalyst was removed byfiltration and the filtrate was concentrated. The residue was purifiedby column chromatography on a silica gel using chloroform-methanol (5:1)as eluent to give (2R)-4-(3-carboxypropyl)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine(0.067 g) as a powder.

mp: 112°-120° C.

α!_(D) ¹⁷ : +3.6° (C=0.5, DMF)

IR (Nujol): 3600-3100, 1700, 1625, 1276, 1175, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.60-5.00 (15H, m); 6.60-8.20 (8H, m); 10.85 (1H, s)

MASS: 542 (M+1)

Example 35

The following compounds were obtained according to a similar manner tothat of Example 34.

1) (2R)-4-(Carboxymethyl)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

mp: 152°-156° C.

α!_(D) ¹⁹ : -3.0° (C=0.5, DMF)

IR (Nujol): 3600-3100, 1654, 1630, 1277, 1196, 1130 cm⁻¹

NMR (DMSO-d₆, δ): 2.20-5.20 (11H, m); 6.60-8.20 (8H, m); 10.85 (1H, s)

MASS: 514 (M+1)

2)(2R)-4-(Carboxymethyl)-2-(1H-indol-3-yl-methyl)-1-(3,5-dimethylbenzoyl)piperazine

mp: 153°-157° C.

α!_(D) ²¹ : +47.0° (C=0.5, DMF)

IR (Nujol): 3600-3150, 1632, 734 cm⁻¹

NMR (DMSO-d₆, δ): 2.05-5.00 (17H, m); 6.50-7.80 (8H, m); 10.83 (1H, s)

MASS: 406 (M+1)

3) (2R)-4-(Carboxymethyl)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(3,4-dimethylbenzyl)piperazine

mp: 120°-135° C.

4) (2R)-4- N-(Carboxymethyl)carbamoylmethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

mp: 172°-175° C.

IR (Nujol): 3700-3100, 1700-1550, 1277, 1171, 1131, 900 cm⁻¹

NMR (DMSO-d₆ ; δ): 2.60-5.00 (13H, m); 6.60-8.20 (9H, m); 10.87 (1H, s)

MASS: 571 (M+1), 456

Example 36

To a mixture of (2R)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4-nitro-trans-cinnamoyl)piperazine(100 mg), powdered sodium hydroxide (30 mg) and cetyltrimethylammoniumbromide (10 mg) in dichloromethane (2 ml) was added 2-dimethylaminoethylchloride hydrochloride (50 mg) at room temperature. The resultingmixture was stirred at the same temperature for 14 hours. After addingdichloromethane (10 ml), the reaction mixture was filtered throughCelite pad and the filtrate was concentrated in vacuo. The resultingresidue was purified by column chromatography on a silica gel elutingwith a mixture of dichloromethane and methanol (30:1) and then treatedwith 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-3,5-bis(-trifluoromethyl)benzoyl!-2-1-(2-dimethylaminoethyl)-1H-indol-3-yl-methyl!-4-(4-nitro-trans-cinnamoyl)piperazinehydrochloride (34 mg).

mp: 171°-175° C.

α!_(D) ²⁴ : -7.80° (C=0.5, MeOH)

IR (Nujol): 3650-3120, 2800-2000, 1635, 1510, 1278, 1171, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.20 (19H, m); 6.50-8.35 (14H, m); 10.51 (1H, brs)

FABMASS: : 702 (M+1) (free), 454

Example 37

The following compounds were obtained according to a similar manner tothat of Example 23.

1) (2R)-4-(Benzyloxycarbonylmethyl)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)piperazinehydrochloride

mp: 115°-120° C.

α!_(D) ¹⁸ : -25.3° (C=0.5, MeOH)

IR (Nujol): 3350 (br), 2700-2300, 1745, 1640, 1500 cm⁻¹

NMR (DMSO-d₆, δ): 2.10 and 2.18 (6H, 2 s); 3.7-5.2 (11H, m); 5.24 (2H,s); 6.6-7.7 (10H, m); 8.18 (1H, br s)

MASS: 593 (M+1) (free), 445

2)(2R)-4-(Methoxycarbonylmethyl)-1-(3,5-dimethylbenzoyl)-2-(3,4-dimethylbenzyl)piperazinehydrochloride

mp: 90°-120° C. (dec.)

α!_(D) ¹⁸ : -39° (C=0.5, MeOH)

IR (Nujol): 3300 (br), 1745, 1630, 1590, 1500 cm-1

NMR (DMSO-d₆, δ): 2.1-2.4 (12H, m); 2.9-5.2 (12H, m); 3.74 (3H, s);6.5-7.3 (6H, m)

MASS: 409 (M+1) (free)

3) (² R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-4-(dimethylamino)benzoyl!piperazine hydrochloride

IR (Nujol): 3350-3220, 2600-2550, 2430-2340, 1622 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.06 (9H, m); 4.68 (6H, s); 6.50-8.30 (13H, m);10.85 (1H, s)

MASS: 603 (M+1) (free)

4) (² R)-⁴ -(4-Aminobenzoyl)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

IR (Nujol): 3260, 2570, 1600-1590 cm⁻¹

NMR (DMSO-d₆, δ): 2.66-3.64 (6H, m); 3.82-5.00 (3H, m); 6.50-8.26 (14H,m); 10.88 (1H, s)

MASS: 575 (M+1) (free)

5) (2R)-4-(Carbamoylmethyl)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

mp: >230° C.

α!_(D) ²¹ : -21.2° (C=0.5, MeOH)

IR (Nujol): 3345, 3140, 2800-2400, 1679, 1655, 1276, 1130, 908 cm⁻¹

NMR (DMSO-d₆, δ): 3.00-5.20 (11H, m); 6.60-8.30 (10H, m); 10.99 (1H, s)

MASS: 513 (M+1) (free), 456

Example 38

To a stirred mixture of (2R)-4-(3-aminopropyl)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-piperazinedihydrochloride (160 mg), nicotinic acid (33 mg) and triethylamine (0.17ml) in dichloromethane (2 ml) was added 2-chloro-1-methylpyridiniumiodide (78 mg) at room temperature. After stirring for 1.5 hours, thereaction mixture was evaporated under reduced pressure. The residue waspartitioned between ethyl acetate (30 ml) and water (10 ml). The organiclayer was separated and dried over magnesium sulfate. After evaporationof the solvent, the residue was purified by column chromatography on asilica gel with dichloromethane-methanol (40:1) as eluent to give(2R)-1- 3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-3-(nicotinoylamino)propyl!-piperazine (70 mg).

α!_(D) ²⁰ : -21.5° (C=1.0, MeOH)

IR (Neat): 3350, 3000-2700, 1630, 1530, 1430, 1380 cm⁻¹

NMR (CDCl₃, δ): 1.7-2.0 (2H, m); 2.18 and 2.21 (6H, 2 s); 2.4-2.6 (2H,m); 2.6-5.2 (11H, m); 6.5-7.5 (7H, m); 7.82 (1H, br s); 8.12 (1H, d,J=8.0 Hz); 8.71 (1H, d, J=3.7 Hz); 8.97 (1H, br s)

MASS: 607 (M+1), 544, 502, 445

Example 39

The following compounds were obtained according to a similar manner tothat of Example 38.

1) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-2-(nicotinoylamino)ethyl!-piperazine

α!_(D) ²⁰ : -17.3° (C=1.0, MeOH)

IR (Neat): 3300, 3050-2700, 1630, 1530, 1430, 1380, 1275 cm⁻¹

NMR (CDCl₃, δ): 2.16 and 2.21 (6H, 2 s); 2.6-2.8 (2H, m); 3.6-3.8 (2H,m); 6.5-7.6 (16H, n); 7.84 (1H, br s); 8.14 (1H, d, J=7.8 Hz); 8.72 (1H,br s); 9.01 (1H, br s)

MASS: 593 (M+1), 530, 473

2) (2R)-4- 2-(N-Acetylamino)thiazol-4-yl!methyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)piperazine

mp: 105°-110° C. (dec.)

α!_(D) ²² : -27.30 (C=1.0, MeOH)

IR (Nujol): 3250, 3180, 3050, 1685, 1635, 1545, 1500, 1350, 1320 cm⁻¹

NMR (CDCl₃, δ): 2.1-2.3 (6H, m); 2.26 (3H, s); 2.6-5.2 (11H, m); 6.4-6.6(1H, m); 6.79 (1H, S); 6.8-7.1 (2H, m); 7.2-7.5 (2H, m); 7.81 (1H, brs); 9.29 (1H, br s)

MASS: 599 (M+1), 445

3) (2R)-4- 2-(Acetylamino)ethyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)piperazinehydrochloride

mp: 90°-105° C. (dec.)

α!_(D) ²⁰ : -23.6° (C=0.5, MeOH)

IR (Nujol): 3250 (br), 2700-2300, 1630, 1530, 1450, 1360, 1270 cm⁻¹

NMR (DMSO-d₆, δ): 1.87 (3H, s); 2.10 and 2.18 (6H, 2 s); 2.6-5.2 (13H,m); 6.6-7.7 (5H, m); 8.1-8.5 (2H, m); 10.9-11.2 (1H, br s)

MASS: 529 (M+1) (free), 445

4) (2R)-4- 3-(Acetylamino)propyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)piperazinehydrochloride

mp: 85°-100° C. (dec.)

α!_(D) ²⁰ : 31 17.5° (C=1.0, MeOH)

IR (Nujol): 3300 (br), 2700-2300, 1630, 1450, 1360, 1270 cm⁻¹

NMR (DMSO-d₆, δ): 1.83 (3H, s); 1.8-2.0 (2H, m); 2.09 and 2.18 (6H, 2s); 2.6-5.2 (15H, m); 7.6-7.3 (3H, m); 7.4-8.3 (3H, m); 11.0-11.4 (1H,m)

MASS: 544 (M+1) (free), 502, 445

5) (2R)-4- 4-(Acetylamino)benzyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

mp: 196°-200° C.

α!_(D) ²¹ : -31.4° (C=0.5, DMF)

IR (Nujol): 3600-3100, 2700-2000, 1640, 1530, 1276, 1175, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.80-5.20 (14H, m); 6.50-8.25 (13H, m); 10.16 (1H, s);10.86 (1H, s)

MASS: 603 (M+1) (free)

6) (2R)-4- 4-(Acetylamino)benzoyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

IR (Nujol): 3250, 1628, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 2.08 (3H, s); 2.90-5.02 (9H, m); 6.54-8.40 (12H, m);10.14 (1H, s); 10.83 (1H, s)

MASS: 617 (M+1)

7) (2R)-4- 3-(Acetylamino)propyl!-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinehydrochloride

IR (Nujol): 3210, 1630, 1544 cm⁻¹

NMR (DMSO-d₆, δ): 1.81 and 1.84 (3H, 2 s); 1.60-2.05 (2H, m); 2.94-5.18(13H, m); 6.57-8.29 (9H, m); 10.97 (1H, s); 11.28 and 11.36 (1H, 2 br s)

MASS: 555 (M+1) (free)

Example 40

To a stirred mixture of (2R)-4-(2-aminoethyl)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-piperazinedihydrochloride (110 mg), triethylamine (0.2 ml) in dichloromethane (10ml) was added methanesulfonyl chloride (0.1 ml) at 0° C. After stirringfor 1 hour, the reaction mixture was poured into ice-water and extractedwith ethyl acetate. The extract was washed successively with aqueoussaturated sodium bicarbonate solution and brine, and dried. Afterevaporation of the solvent in vacuo, the residue was purified by columnchromatography on a silica gel eluting with a mixture of dichloromethaneand methanol (40:1) and treated with 4N hydrogen chloride in ethylacetate solution to give (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-2-(mesylamino)ethyl!piperazine hydrochloride (50 mg).

mp: >220° C.

α!_(D) ²² : +0.2° (C=0.5, DMF)

IR (Nujol): 3350, 2700-2400, 1645, 1500, 1450, 1380 cm⁻¹

NMR (DMSO-d₆, δ): 2.10 and 2.18 (6H, 2 s); 2.7-5.2 (17H, m); 6.6-7.7(5H, m); 8.1-8.2 (1H, m); 11.05-11.4 (1H, m)

MASS: 566 (M+1) (free)

Example 41

The following compounds were obtained according to a similar manner tothat of Example 40.

1) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-4-(mesylamino)benzyl!piperazine hydrochloride

mp: 152°-165° C.

α!_(D) ²³ : -32.2° (C=0.5, DMF)

IR (Nujol): 3600-3100, 2750-2000, 1635, 1278, 1172, 1140, 900 cm⁻¹

NMR (DMSO-d₆, δ): 3.00-5.10 (14H, m); 6.50-8.25 (13H, m); 10.03 (1H, s);10.85 (1H, s)

MASS: 639 (M+1) (free), 456

2) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-3-(mesylamino)propyl!piperazine hydrochloride

mp: 165°-180° C.

α!_(D) ²² : -0.7° (C=1.0, DMF)

IR (Nujol): 3350, 2700-2400, 1645, 1500, 1450, 1380 cm⁻¹

NMR (DMSO-d₆, δ): 1.8-2.1 (2H, m); 2.09 and 2.18 (6H, 2 s); 2.6-5.2(17H, m); 6.68 (1H, br s); 7.0-7.4 (2H, m); 7.42 and 7.69 (2H, 2 s);8.1-8.2 (1H, m); 11.0-11.4 (1H, m)

MASS: 580 (M+1) (free), 445

3) (2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-4-(mesylamino)benzoyl!piperazine

IR (Nujol): 3260-3170, 1627 cm⁻¹

NMR (DMSO-d₆, δ): 3.06 (3H, s); 2.60-3.66 (6H, m); 3.84-5.02 (3H, m);6.52-8.44 (12H, m); 10.05 (1H, s); 10.83 (1H, s)

MASS: 653 (M+1)

4) (2R)-1-3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(phenylsulfonyl)piperazine

α!_(D) ²¹ : +46.1° (C=1.0, MeOH)

IR (Neat): 3500-3100, 1635, 1276, 1165, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.20-5.00 (9H, m); 6.40-8.20 (13H, m); 10.90 (1H, brs)

MASS: 596 (M+1)

Example 42

A mixture of (2R)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)-4-(phthalimidomethyl-carbonyl)piperazine(250 mg), hydrazine hydrate (50 mg) in ethanol (5 ml) was heated underreflux for 2 hours. The resulting precipitate was removed by filtrationand the filtrate was evaporated under reduced pressure. The residue waswashed with aqueous 1N sodium hydroxide solution and then purified bycolumn chromatography on a silica gel eluting with a mixture of ethylacetate and methanol (4:1) to afford (2R)-4-(2-aminoacetyl)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine (110mg).

mp: 110°-120° C.

α!_(D) ²¹ : -4.4° (C=1.0, MeOH)

IR (Nujol): 3600-3100, 1634, 1277, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.20 (13H, m); 6.55-8.30 (8H, m); 10.87 (1H, brs)

MASS: 513 (M+1), 456

Example 43

The following compounds were obtained according to a similar manner tothat of Example 42.

1) (2R)-4-(3-Aminopropyl)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(3,4-dimethylbenzyl)piperazinedihydrochloride

mp: 98°-1050° C. (dec.)

α!_(D) ²⁰ : 31 18.8° (C=0.5, DMF)

IR (Nujol): 3300 (br), 2900-2500, 1630, 1500, 1430, 1380, 1350 cm⁻¹

NMR (DMSO-d₆, δ): 2.09 and 2.18 (6H, 2 s); 1.6-5.0 (1SH, m); 6.6-7.7(6H, m); 7.9-8.3 (4H, m)

MASS: 502 (M+1) (free), 445

2) (2R)-4-(2-Aminoethyl)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(3,4-dimethylbenzyl)piperazinedihydrochloride

mp: 160°-170° C. (dec.)

α!_(D) ²⁰ : -0.8° (C=0.5, DMF)

IR (Nujol): 3300 (br), 2700-2500, 1630, 1500, 1430, 1360 cm⁻¹

NMR (DMSO-d₆, δ): 2.10 and 2.19 (6H, 2 s); 2.6-5.2 (13H, m); 6.6-7.7(5H, m); 8.2-8.3 (1H, m); 8.1-8.8 (4H, br m)

MASS: 488 (M+1) (free), 445

Example 44

A mixture of (2R)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4-nitrobenzyl)-piperazine(360 mg), iron powder (360 mg), ammonium chloride (36 mg) and water (1.5ml) in ethanol (6 ml) was heated under reflux for 40 minutes. Aftercooling, the reaction mixture was filtered and the filtrate wasevaporated under reduced pressure. The residue was purified by columnchromatography on a silica gel eluting with a mixture of dichloromethaneand methanol (10:1) to give (2R)-4-(4-aminobenzyl)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)piperazine(0.34 g).

α!_(D) ¹⁸ : -35.8° (C=0.5, DMF)

IR (Neat): 3500-3100, 1623, 1514, 1274, 1170, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.90-4.90 (11H, m); 4.97 (2H, s); 6.50-8.20 (12H, m);10.80 (1H, s)

MASS: 561 (M+1), 456

Example 45

The following compound was obtained according to a similar manner tothat of Example 44.

(2R)-4-(4-Aminobenzoyl)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)piperazine

IR (Neat): 3330, 3000, 2910, 1625-1600, 1515 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-3.64 (SH, m); 3.80-4.40 (4H, m); 4.79-5.70 (2H,m); 6.43-8.40 (12H, m); 10.85 (1H, s)

MASS: 575 (X+1)

Example 46

A solution of 4N hydrogen chloride in ethyl acetate solution (1.5 ml)was added dropwise to a solution of (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(4-trityl-1-piperazinyl)carbonymethyl!-piperazine (480 mg) in ethylacetate (5 ml) at 0° C. The resulting mixture was stirred at the sametemperature for 1 hour and then allowed to stand overnight. Aqueoussaturated sodium bicarbonate solution (20 ml) was added to the reactionmixture, and the product was extracted with ethyl acetate. The organicphase was washed with brine and dried. After evaporation of the solventin vacuo, the residue was purified by column chromatography on a silicagel eluting with a mixture of dichloromethane and methanol (5:1) andtreated with 4N hydrogen chloride in dioxane solution to afford(2R)-1-t3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)-4-(l-piperazinyl)-carbonylmethyl!piperazine dihydrochloride (250 mg).

mp: 210°-218° C.

α!_(D) ¹⁹ : -25.60 (C=0.5, DMF)

IR (Nujol): 3650-3100, 2700-2000, 1645, 1275, 1174, 1130, 902 cm⁻¹

NMR (DMSO-d₆, δ): 3.00-5.20 (20H, m); 6.60-8.30 (8H, m); 9.73 (2H, brs); 10.99 (1H, s)

MASS: 582 (X+1) (free)

Example 47

A mixture of (2R)-1-3,5-bis(trifluoromethyl)-benzoyl!-4-(2-chloroacetyl)-2-(1H-indol-3-yl-methyl)piperazine(730 mg), potassium phthalimide (260 mg) in dimethylformamide (10 ml)was stirred at room temperature for 7 hours and then poured into aqueoussodium chloride solution (100 ml). The resulting precipitate wascollected by filtration, washed with water and dried. The crude productwas dissolved in toluene (7 ml) and filtered. To the filtrate was addedn-hexane (35 ml) and the whole was stirred for 10 minutes. The resultingpowder was collected by filtration, washed with ethyl ether and dried togive (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(phthalimidomethylcarbonyl)piperazine (500 mg).

mp: >220° C.

α!_(D) ¹⁹ : -1.2° (C=O.5, DMF)

IR (Nujol): 3500-3200, 1772, 1708, 1647, 1275, 1183, 1131, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.50-5.20 (11H, m); 6.60-8.30 (12H, m); 10.83-10.94(1H, m)

MASS: 643 (M+1)

Example 48

A mixture of (2R)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)piperazine(150 mg), acrylamide (24 mg) in toluene (1.5 ml) was stirred at roomtemperature for 1 hour and then was refluxed for 5 hours. Afteradditional acrylamide (24 mg) was added, the whole mixture was refluxedfor 3 hours and evaporated under reduced pressure. The obtained residuewas purified by column chromatography on a silica gel eluting with amixture of ethyl acetate and methanol (10:1) to give (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-4-(2-carbamoylethyl)-2-(1H-indol-3-yl-methyl)piperazine(89 mg).

mp: 80°-100° C.

α!_(D) ¹⁷ : +3.6° (C=0.5, DMF)

IR (Nujol): 3600-3100, 1673, 1636, 1276, 1170, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.00-4.90 (13H, m); 6.60-8.20 (10H, m); 10.84 (1H, s)

MASS: 527 (M+1), 456

Example 49

To a stirred solution of (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(2-chloroacetyl)piperazine(300 mg) in tetrahydrofuran (5 ml) was added N-methylbenzylamine (140mg) at room temperature. After stirring for 2 hours, additionalN-methylbenzylamine (70 mg) was added, and then the whole was heated at45° C. for 6 hours. The mixture was concentrated in vacuo and theresidue was partitioned between ethyl acetate (20 ml) and aqueous sodiumbicarbonate solution (10 ml). The organic layer was separated and driedover magnesium sulfate. After evaporation of the solvent in vacuo, theresidue was purified by column chromatography on a silica gel elutingwith a mixture of dichloromethane and methanol (50:1) and treated with4N hydrogen chloride in ethyl acetate solution to afford (2R)-1-3,5-bis(trifluoromethyl)-benzoyl!-4-2-(N-benzyl-N-methylamino)acetyl!-2-(3,4-dimethylbenzyl)piperazinehydrochloride (0.35 g).

mp: 207°-208° C.

α!_(D) ²⁴ : -1.40° (C=1.0, MeOH)

IR (Nujol): 3350 (br), 2700-2600, 1635, 1450, 1370, 1350, 1330 cm⁻¹

NMR (DMSO-d₆, δ): 2.10 and 2.18 (6H, 2 s); 2.7-5.1 (16H, m); 6.5-6.8(1H, m); 6.9-7.3 (2H, m); 7.4-7.7 (7H, m); 8.1-8.3 (1H, m); 10.0-10.4(1H, m)

MASS: 606 (M+1) (free), 445

Example 50

The following piperazine derivatives (Table 1) were prepared by thesimilar manner to that of the each Example No. defined in the "Process"column. The physical properties of the object compounds are shown afterthe table. ##STR36##

                                      TABLE 1    __________________________________________________________________________    Example         Object Compounds           Starting    No.  R.sup.4               Salt Compound                                          Process    __________________________________________________________________________    50-1)         (CH.sub.2).sub.4 NHSO.sub.2 CH.sub.3                               HCl  Ex. 50-21)                                          Ex. 40    50-2)                               HCl  Ex. 50-20)                                          Ex. 40    50-3)         (CH.sub.2).sub.3 NHCOOC.sub.2 H.sub.5                               HCl  Ex. 50-20)                                          Ex. 40    50-4)          ##STR37##            HCl  Ex. 50-20)                                          Ex. 40    50-5)         (CH.sub.2).sub.3 NHCOCOOC.sub.2 H.sub.5                               HCl  Ex. 50-20)                                          Ex. 40    50-6)          ##STR38##            HCl  Ex. 50-20)                                          Ex. 40    50-7)         (CH.sub.2).sub.3 NHSO.sub.2 CH.sub.3                               HCl  Ex. 50-20)                                          Ex. 40    50-8)          ##STR39##            HCl  Ex. 50-20)                                          Ex. 38    50-9)          ##STR40##            HCl  Ex. 50-20)                                          Ex. 38    50-10)          ##STR41##            HCl  Ex. 50-20)                                          Ex. 38    50-11)          ##STR42##            HCl  Ex. 50-20)                                          Ex. 38    50-12)         (CH.sub.2).sub.2 NHSO.sub.2 CH.sub.3                               HCl  Ex. 65                                          Ex. 40    50-13)          ##STR43##            --   Ex. 6 Ex. 14    50-14)         CH.sub.2 CN           --   Ex. 6 Ex. 11    50-15)         (CH.sub.2).sub.3 CN   --   Ex. 6 Ex. 11    50-16)          ##STR44##            --   Ex. 6 Ex. 11    50-17)          ##STR45##            --   Ex. 6 Ex. 11    50-18)         CH.sub.2 CN           HCl  Ex. 50-14)                                          Ex. 23    50-19)         (CH.sub.2).sub.3 CN   HCl  Ex. 50-15)                                          Ex. 23    50-20)         (CH.sub.2).sub.3 NH.sub.2                               2HCl Ex. 50-16)                                          Ex. 42    50-21)         (CH.sub.2).sub.4 NH.sub.2                               2HCl Ex. 50-17)                                          Ex. 42    50-22)          ##STR46##            HCl  Ex. 50-20)                                          Ex. 62    50-23)          ##STR47##            --   Ex. 6 Ex. 16    50-24)          ##STR48##            --   Ex. 50-23)                                          Ex. 10    50-25)         CH.sub.2 CONHNHCONH.sub.2                               --   Ex. 35-1)                                          Ex. 27    50-26)          ##STR49##            --   Ex. 6 Ex. 63    50-27)          ##STR50##            --   Ex. 35-1)                                          Ex. 27    50-28)         (CH.sub.2).sub.3 CONHOCH.sub.3                               HCl  Ex. 34                                          Ex. 27    50-29)          ##STR51##            --   Ex. 34                                          Ex. 27    50-30)         (CH.sub.2).sub.3 CONHCH.sub.3                               --   Ex. 34                                          Ex. 27    50-31)         CH.sub.2 CONHOCH.sub.3                               --   Ex. 35-1)                                          Ex. 27    50-32)          ##STR52##            --   Ex. 6 Ex. 11    50-33)          ##STR53##            --   Ex. 50-32)                                          Ex. 44    50-34)          ##STR54##            --   Ex. 50-33)                                          Ex. 40    50-35)         CO(CH.sub.2).sub.3 N(CH.sub.3).sub.2                               HCl  Ex. 61                                          Ex. 23    50-36)          ##STR55##            --   Ex. 6 Ex. 11    50-37)          ##STR56##            --   Ex. 50-36)                                          Ex. 10    50-38)          ##STR57##            --   Ex. 50-37)                                          Ex. 27    50-39)          ##STR58##            --   Ex. 50-37)                                          Ex. 27    50-40)          ##STR59##            HCl  Ex. 50-37)                                          Ex. 27    50-41)          ##STR60##            --   Ex. 6 Ex. 11    50-42)          ##STR61##            citric acid                                    Ex. 32-41)                                          Ex. 23    50-43)          ##STR62##            --   Ex. 50-41)                                          Ex. 10    50-44)          ##STR63##            --   Ex. 50-41)                                          Ex. 27    50-45)          ##STR64##            --   Ex. 6 Ex. 11    50-46)          ##STR65##            --   Ex. 50-45)                                          Ex. 44    50-47)          ##STR66##            --   Ex. 50-46)                                          Ex. 40    50-48)          ##STR67##            H.sub.2 SO.sub.4                                    Ex. 32-52)                                          Ex. 23    50-49)          ##STR68##            HCl  Ex. 34                                          Ex. 72    50-50)          ##STR69##            2HCl Ex. 34                                          Ex. 72    50-51)          ##STR70##            2HCl Ex. 34                                          Ex. 72    50-52)          ##STR71##            2HCl Ex. 34                                          Ex. 72    50-53)          ##STR72##            HCl  Ex. 34                                          Ex. 72    50-54)          ##STR73##            3HCl Ex. 34                                          Ex. 72    50-55)          ##STR74##            HCl  Ex. 34                                          Ex. 72    50-56)          ##STR75##            --   Ex. 34                                          Ex. 72    50-57)          ##STR76##            2HCl Ex. 50-56)                                          Ex. 46    50-58)          ##STR77##            H.sub.2 SO.sub.4                                    Ex. 34                                          Ex. 72    __________________________________________________________________________

Physical properties of the compounds of the Example 50:

Example 50-1)

IR (Nujol): 3260-3170, 1635 cm⁻¹

NMR (DMSO-d₆,δ): 1.40-1.94 (4H, m); 2.80-5.20 (13H, m); 2.90, 2.92 (3H,2 s); 6.60-8.30 (9H, m); 10.95 (1H, s); 10.86-11.32 (1H, m)

MASS: 605 (M+1) (free)

Example 50-2)

IR (Nujol): 3230, 2570, 1638, 1596 cm⁻¹

NMR (DMSO-d₆, δ): 1.90-2.20 (2H, m); 3.00-5.20 (13H, m); 6.59-8.40 (12H,m); 8.98-9.13 (1H, m); 10.96 (1H, s); 10.95-11.34 (1H, m)

MASS: 662 (M+1) (free)

Example 50-3)

IR (Nujol): 3260, 2560, 1697, 1635 cm⁻¹

NMR (DMSO-d₆, δ): 1.07-1.23 (3H, m); 1.70-2.05 (2H, m); 2.95-5.18 (15H,m); 6.60-8.30 (9H, m); 10.96 (1H, s); 11.00-11.38 (1H, m)

MASS: 585 (M+1) (free)

Example 50-4)

IR (Nujol): 3230, 2560, 1635, 1574, 1531 cm⁻¹

NMR (DMSO-d₆, δ): 1.82-2.18 (2H, m); 2.94-5.24 (13H, m); 6.57-8.29 (13H,m); 8.63-8.80 (1H, m); 10.96 (1H, s); 10.86-11.27 (1H, m)

MASS: 617 (M+1) (free)

Example 50-5)

IR (Nujol): 3240, 2560, 1734, 1685, 1635, 1523 cm⁻¹

NMR (DMSO-d₆, δ): 1.28 (3H, t, J=7.06 Hz); 1.75-2.14 (2H, m); 2.88-4.16,4.49-4.67, 5.02-5.21 (13H, m) ; 4.24 (2H, q, t=7.06 Hz); 6.57-8.29 (8H,m)); 9.11 (1H, m)); 10.96 (1H, s); 11.03-11.35 (1H, m)

MASS: 613 (M+1) (free)

Example50-6)

IR (Nujol): : 3350-3200, 1636 cm⁻¹

NMR (DMSO-d₆, δ): 1.89-2.08 (2H, m); 2.70-2.94 (2H, m); 2.94-4.15,4.50-4.68, 5.00-5.20 (11H, m)); 6.57-8.31 (14H, m); 10.96 (1H, s);11.05-11.40 (1H, m)

MASS: 653 (M+1) (free)

Example 50-7)

IR (Nujol): 3150, 1601 cm⁻¹

NMR (DMSO-d₆, δ): 1.82-2.14 (2H, m); 2.92, 2.94 (3H, s); 2.96-4.17,4.50-4.70, 5.04-5.20 (13H, m); 6.60-8.28 (9H, m); 10.94 (1H, s); 11.25,11.40 (1H, br s)

MASS: 591 (M+1) (free)

Example 50-8)

IR (Nujol): 3240, 1677, 1635, 1538 cm⁻¹

NMR (DMSO-d₆, δ): 1.85-2.20 (2H, m); 2.62 (3H, s); 3.00-4.23, 4.49-4.67,5.05-5.21 (13H, m); 6.12-8.27 (12H, m); 8.91 (1H, m); 10.94 (1H, s);11.04-11.37 (1H, m)

MASS: 659 (M+1) (free)

Example 50-9)

IR (Nujol): 3250, 1638 cm⁻¹

NMR (DMSO-d₆, δ): 1.82-2.24 (2H, m); 2.90-5.20 (13H, m); 6.55-8.28 (12H,m); 8.90-9.10 (1H, m); 10.96 (1H, s); 10.84-11.34 (1H, m)

MASS: 642 (M+1) (free)

Example 50-10)

IR (Nujol): 3230, 1634 cm⁻¹

NMR (DMSO-d₆, δ): 1.87-2.20 (2H, m); 2.94-5.24 (13H, m); 6.56-8.29 (12H,m); 8.66-8.88 (1H, m); 10.96 (1H, s); 10.90-11.33 (1H, m)

MASS: 635 (M+1) (free)

Example 50-11)

IR (Nujol): 3240, 2710-2570, 1630, 1540 cm⁻¹

NMR (DMSO-d₆, δ): 1.89-2.20 (2H, m); 3.00-5.20 (13H, m); 3.83 (3H, s);6.59-8.26 (14H, m); 10.95 (1H, s); 10.84-11.28 (1H, m)

MASS: 670 (M+1) (free)

Example 50-12)

IR (Nujol): 3250, 1634 cm⁻¹

NMR (DMSO-d₆, δ): 2.98, 3.01 (3H, 2 s); 2.60-5.18 (13H, m); 6.54-8.25(9H, m); 10.95 (1H, s); 11.12-11.52 (1H, m)

MASS: 577 (M+1) (free)

Example 50-13)

IR (Neat): 3240, 3040, 2910, 1653-1612 cm⁻¹

NMR (CDCl₃, δ): 2.20-4.10 (13H, m); 6.77-8.44 (15H, m)

MASS: 603 (M+1)

Example 50-14)

IR (CHCl₃): 3270, 2990, 2920, 2220, 1714, 1661-1610 cm⁻¹

NMR (DMSO-d₆, δ): 2.20-3.45, 3.70-4.00, 4.26-4.44, 4.85-5.05 (11H, m);6.55-8.24 (8H, m); 10.87 (1H, s)

MASS: 495 (M+1)

Example 50-15)

IR (Neat): 3280, 2230, 1664, 1626 cm⁻¹

NMR (DMSO-d₆, 6): 1.64-2.44 (4H, m); 2.54-4.97 (11H, m); 6.56-8.25 (8H,m); 10.86 (1H, s)

MASS: 523 (M+1)

Example 50-16)

IR (Neat): 3270, 2920, 1766, 1703, 1667, 1630 cm⁻¹

NMR (DMSO-d₆, δ): 1.70-2.45 (4H, m); 2.78-4.92 (11H, m); 6.54-8.22 (12H,m); 10.83 (1H, s)

MASS: 643 (M+1)

Example 50-17)

IR (CHC1₃): 3300, 2920, 1766, 1706, 1627 cm⁻¹

NMR (DMSO-d₆, δ): 1.35-1.82 (4H, m); 1.85-2.44 (2H, m); 2.70-4.35,4.76-4.94 (11H, m); 6.56-8.22 (12H, m); 10.84 (1H, s)

MASS: 657 (M+1)

Example 50-18)

IR (Neat): 3280, 2910, 2210, 1740, 1630 cm⁻¹

NMR (DMSO-d₆, δ) 2.20-5.06 (11H, m); 6.54-8.24 (8H, m); 10.89 (1H, s);10.75-11.03 (1H, m)

MASS: 495 (M+1) (free)

Example 50-19)

IR (Nujol): 3360-3230, 2710-2230, 1635 cm⁻¹

NMR (DMSO-d₆, δ): 2.00-2.27 (2H, m); 2.58-2.80 (2H, m); 2.96-5.19 (11H,m); 6.56-8.28 (8H, m); 10.94 (1H, s); 11.36-11.73 (1H, m)

MASS: 523 (M+1) (free)

Example 50-20)

IR (Nujol): 3450, 1635 cm⁻¹

NMR (DMSO-d₆, δ): 1.96-2.28 (2H, m); 2.75-5.22 (13H, m); 6.56-8.30 (11H,m); 10.96 (1H, s); 11.54-11.88 (1H, m)

MASS: 513 (M+1) (free).

Example 50-21)

IR (Nujol): 3340, 1635 cm⁻¹

NMR (DMSO-d₆, δ): 1.50-2.00 (4H, m); 2.68-5.20 (13H, m); 6.56-8.28 (11H,m); 10.96 (1H, s); 11.54 (1H, br s)

MASS: 527 (M+1) (free)

Example 50-22)

IR (Nujol): 3270, 1637, 1595 cm⁻¹

NMR (DMSO-d₆, δ): 1.68-2.10 (2H, m); 3.00-3.74, 4.02-4.19, 4.49-4.68,5.05-5.20 (13H, m); 6 43-8.28 (14H, m); 8.75, 8.81 (1H, s); 10.95 (1H,s); 10.72-11.00 (1H, m)

MASS: 632 (M+1) (free)

Example 50-23)

IR (Neat): 3250, 2980, 2900, 1714, 1625, 1575 cm⁻¹

NMR (DMSO-d₆, δ): 2.87-5.03 (9H, m); 3.89 (3H, s); 6.45-8.26 (12H, m);10.78, 10.89 (1H, 2 br s)

MASS: 618 (M+1)

Example 50-24)

IR (Neat): 3330-3220, 2960, 1612, 1540 cm⁻¹

NMR (DMSO-d₆, δ): 2.83-4.43 (10H, m); 6.54-8.22 (12H, m); 10.88 (1H, s)

MASS: 604 (M+1)

Example 50-25)

mp: >220° C.

α!_(D) ²⁴ : -11.2° (C=0.5, DMF)

IR (Nujol): 3360, 3180, 1715, 1656, 1630, 1273, 1190, 1120, 903 cm⁻¹

NMR (DMSO-d₆, δ): 2.05-5.00 (11H, m); 5.94 (2H, s); 6.60-8.20 (9H, m);9.50 (1H, s); 10.83 (1H, s)

MASS: 571 (M+1)

Example 50-26)

IR (Neat): 3260, 2920, 2850, 1626 cm⁻¹

NMR (DMSO-d₆, δ): 0.88 (3H, t, J=7.2 Hz); 1.10-1.63 (4H, m); 2.85 (3H,s); 2.69-5.05 (11H, m); 6.57-8.30 (8H, m); 10.88 (1H, s)

MASS: 569 (M+1)

Example 50-27)

α!_(D) ²¹ : -4.6° (C=1.0, MeOH)

IR (Neat): 3300, 1630, 1430, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 2.20-4.90 (11H, m); 3.13 (3H, s); 3.71 (3H, s);6.60-8.20 (8H, m); 10.86 (1H, s)

MASS: 557 (M+1)

Example 50-28)

α!_(D) ²¹ : -7.0° (C=1.0, MeOH)

IR (Neat): 3150, 2550, 2440, 2325, 1640, 1430, 1355, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 2.0-5.20 (15H, m); 3.60 (3H, s); 6.17-8.23 (8H, m);10.97 (1H, s); 11.3 (1H, br s)

MASS: 571 (M+1) (free)

Example 50-29)

α!_(D) ²⁰ : -14.7° (C=1.0, MeOH)

IR (Neat): 3260, 1625, 1430, 1350, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 1.60-4.95 (23H, m); 2.16 (3H, s); 6.6-8.19 (8H, m);10.87 (1H, s)

MASS: 624 (M+1)

Example 50-30)

α!_(D) ²⁰ : -10.5° (C=1.0, MeOH)

IR (Neat): 3260, 1650, 1630, 1570, 1430, 1350, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 1.63-4.90 (15H, m); 2.59 (2H, d); 6.15-8.20 (9H, m);10.87 (1H, s)

MASS: 555 (M+1)

Example 50-31)

α!_(D) ²⁰ : -6.2° (C=1.0, MeOH)

IR (Neat): 3250, 1670, 1625, 1430, 1350, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 2.0-4.85 (9H, m); 2.97 (2H, s); 3.63 (3H, s);6.63-8.18 (8H, m); 10.86 (1H, s); 11.15 (1H, s)

MASS: 543 (M+1)

Example 50-32)

α!_(D) ²¹ : -18.9° (C=1.0, MeOH)

IR (Neat): 3300, 1690, 1625, 1525, 1430, 1345, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 2.2-4.93 (11H, m); 6.54-8.48 (13H, m); 10.83 (1H, s)

MASS: 619 (M+1)

Example 50-33)

α!_(D) ²¹ : -34.8° (C=1.0, MeOH)

IR (Neat): 3350, 1620, 1590, 1440, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 2.1-4.96 (11H, m); 5.94-8.26 (13H, m); 10.82 (1H, s)

MASS: 589 (M+1)

Example 50-34)

α!_(D) ³⁰ : -18.9° (C=1.0, MeOH)

IR (Neat): 3400, 1685, 1625, 1365, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 1.99 (3H, s); 2.10-4.93 (11H, m); 6.53-8.28 (12H, m);10.81 (1H, s)

MASS: 667 (M+1)

Example 50-35)

IR (Nujol): 3350-3200, 2710, 1624 cm⁻¹

NMR (DMSO-d₆, δ): 1.77-2.10 (2H, m); 2.28-5.18 (13H, m); 2.74, 2.76 (6H,2 s); 6.55-8.24 (8H, m); 10.51 (1H, br s); 10.93 (1H, s)

MASS: 569 (M+1) (free)

Example 50-36)

IR (Neat): 3300, 1720, 1630, 1430, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 1.1-1.32 (6H, m); 2.2-4.93 (13H, m); 6.57-8.21 (8H,m); 10.84 (1H, s)

MASS: 556 (M+1)

Example 50-37)

α!_(D) ²⁰ : -23.3° (C=1.0, MeOH)

IR (Neat): 3300, 1730, 1640, 1460, 1375, 1280 cm⁻¹

NMR (DMSO-d₆, δ): 1.4-1.6 (3H, m) ; 2.8-5.1 (10H, m); 6.6-8.26 (8H, m) ;10.93 (1H, s)

MASS: 528 (M+1)

Example 50-38)

IR (Neat): 3250, 1670, 1625, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 1.04-1.25 (3H, m); 2.16-4.90 (10H, m); 3.61 (3H, s);6.60-8.27 (8H, m); 10.84 (1H, s); 11.09 (1H, s)

MASS: 557 (M+1)

Example 50-39)

α!_(D) ¹⁹ : -8.8° (C=1.0, MeOH)

IR (Neat): 3300, 1680, 1630, 1280 cm⁻¹

NMR (DMSO-d₆, δ): 1.0-1.2 (3H, m); 2.10-4.93 (10H, m); 6.6-8.24 (8H, m);10.83 (1H, s)

MASS: 527 (M+1)

Example 50-40)

α!_(D) ¹⁹ : -16.5° (C=1.0, MeOH)

IR (Neat): 3300, 1630, 1460, 1370, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 0.94-1.15 (3H, m); 2.15-5.0 (18H, m); 6.6-8.2 (8H, m);10.88 (1H, s); 11.30 (1H, br s)

MASS: 610 (M+1) (free)

Example 50-41)

one isomer

α!_(D) ¹⁹ : +18.8° (C=1.0, MeOH)

IR (Nujol): 3240, 1745, 1630, 1450, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 2.0-4.9 (10H, m); 3.62 (3H, s); 6.52-8.2 (13H, m);10.8 (1H, s)

MASS: 604 (M+1)

the other isomer

α!_(D) ¹⁹ : -44.9° (C=1.0, MeOH)

IR (Neat):. 3300, 1730, 1625, 1275 cm¹

NMR (DMSO-d₆, 6): 2.10-4.88 (10H, m); 3.65 (3H, s) 6.57-8.25 (13H, m);10.77 (1H, s)

MASS: 604 (M+1)

Example 50-42)

mp: 194°-198° C. (dec.)

α!_(D) ²⁹ : -11.2° (C=0.5, DMF)

IR (Nujol): 3700-3150, 3000-2100, 1726, 1637, 1274, 1131; 896 cm⁻¹

NMR (DMSO-d₆, δ): 1.80-4.40 (24H, m); 6.50-8.20 (8H, m); 10.85 (1H, s)

MASS: 610 (M+1) (free)

Example 50-43)

IR (Nujol): 3300, 1710, 1680, 1455, 1280 cm⁻¹

NMR (DMSO-d₆, δ): 2.0-4.9 (1OH, m); 6.5-8.28 (13H, m); 10.8 (2H,d)

Example 50-44)

one isomer

α!_(D) ²¹ : -10.1° (C=1.0, MeOH)

IR (Neat): 3200, 1670, 1620, 1450, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 1.86-4.86 (18H, m); 2.15 (3H, s); 6.5-8.69 (13H, m);9.24 (1H, s); 10.79 (1H, s)

MASS: 687 (M+1)

the other isomer

α!_(D) ²¹ : +11.2° (C=1.0, MeOH)

IR (Neat): 3200, 1650, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 1.83-4.83 (18H, m); 2.16 (3H, s); 6.55-8.6 (13H, m);9.2 (1H, s); 10.86 (1H, s)

MASS: 687 (M+1)

Example 50-45)

one isomer

α!_(D) ²⁰ : +19.2° (C=1.0, MeOH)

IR (Neat): 3400, 1730, 1630, 1520, 1345, 1280 cm⁻¹

NMR (DMSO-d₆, δ): 2.10-4.93 (10H, m); 3.66 (3H, s); 6.55-8.34 (12H, m);10.84 (1H, s)

MASS: 649 (M+1)

the other isomer

IR (Neat): 3400, 1730, 1630, 1520, 1345, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 2.05-4.93 (10H, m); 3.69 (3H, s); 6.52-8.31 (12H, m);10.80 (1H, s)

MASS: 649 (M+1)

Example 50-46)

α!_(D) ²⁰ : -98.5° (C=1.0, MeOH)

IR (Nujol): 3425, 3325, 1720, 1640, 1510, 1460, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 1.9-4.85 (10H, m); 3.63 (3H, s); 5.15 (2H, s);6.52-8.18 (12H, m); 10.8 (1H, s)

MASS: 619 (M+1)

Example 50-47)

α!_(D) ²⁰ : -64.3° (C=1.0, MeOH)

IR (Neat): 3400, 3250, 1730, 1625, 1510, 1330, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 1.99 (3H, s); 2.0-5.20 (10H, m); 3.0 (3H, s);6.52-8.19 (12H, m); 9.85 (1H, s);. 10.76 (1H, s)

MASS: 697 (M+1)

Example 50-48)

α!_(D) ²⁰ : -11.0° (C=1.0, MeOH)

IR (Nujol): 3350, 3150, 2650, 2450, 2300, 1635, 1270 cm⁻¹

NMR (DMSO-d₆, δ): 1.60-4.93 (26H, m); 6.60-8.66 (8H, m); 9.18 (1H, s) ;10.87 (1H, s)

MASS: 639 (M+1)

Example 50-49)

IR (Nujol): 3200, 1626 cm⁻¹

NMR(DMSO-d₆, δ): 1.86-2.12 (7H, m); 2.34-2.59 (4H, m); 2.82-5.20 (15H,m); 6.60-8.28 (13H, m); 10.96 (1H, s); 10.87-11.35 (1H, m)

MASS: 699 (M+1) (free)

Example 50-50)

IR (Nujol): 3350-3210, 2550-2500, 1635 cm⁻¹

NMR (DMSO-d₆, δ): 1.76-2.20 (2H, m); 2.37-2.66 (2H, m); 2.80-5.20 (19H,m); 6.59-8.30 (13H, m); 10.97 (1H, s); 10.87-11.55 (2H, m)

MASS: 686 (M+1) (free)

Example 50-51)

IR (Nujol): 3350-3250, 2580, 1630 cm⁻¹

NMR (DMSO-d₆, δ): 0.95-2.20 (12H, m); 2.76-5.20 (22H, m); 6.54-8.30 (8H,m); 10.96 (1H, s) ; 10.79-11.17 (1H, m); 11.42 (1H, br s)

MASS: 692 (M+1) (free)

Example 50-52)

IR (Neat): 3330, 2680, 1630, 1540 cm⁻¹

NMR (DMSO-d₆, δ): 1.75-2.37 (4H, m); 2.76, 2.78 (6H, 2 s); 2.92-5.20(15H, m); 6.55-8.47 (9H, m); 10.37 (1H, br s); 10.97 (1H, s);11.15-11.57 (1H, br s)

MASS: 612 (M+1) (free)

Example 50-53)

IR (Nujol): 3200, 1626 cm⁻¹

NMR (DMSO-d₆, δ): 1.20-1.67 (6H, m); 1.72-2.12 (2H, m); 2.23-2.52 (2H,m); 2.75-5.18 (15H, m)); 6.57-8.27 (8H, m); 10.95 (1H, s); 10.80-11.36(1H, m)

MASS: 609 (M+1) (free)

Example 50-54)

IR (Nujol): 3350-3230, 1640 cm⁻¹

NMR (DMSO-d₆, δ): 1.92-2.14 (2H, m); 2.44-2.66 (2H, m); 2.96-5.20(19H,m); 6.57-8.26 (12H, m); 10.97 (1H, s); 10.88-11.04 (2H, m); 11.36-11.65(1H, m)

MASS: 687 (M+1) (free)

Example 50-55)

IR (Nujol): 3400-3220, 2550, 1625 cm⁻¹

NMR (DMSO-d₆, δ): 1.29-2.26 (6H, m); 2.38-5.22 (18H, m); 6.58-8.30 (13H,m); 10.96 (1H, s); 10.79-11.30 (1H, m)

MASS: 685 (M+1) (free)

Example 50-56)

IR (Neat): 3260, 2990, 2810, 1625 cm⁻¹

NMR (DMSO-d₆, δ): 1.47-2.22 (9H, m); 2.58-4.96 (14H, m); 6.56-8.26 (23H,m); 10.85 (1H, s)

MASS: 852 (M+1)

Example 50-57)

IR (Nujol): 3330, 2700, 1630 cm⁻¹

NMR (DMSO-d₆, δ): 1.80-2.23 (2H, m); 2.33-2.66 (2H, m); 2.90-5.20 (19H,m)); 6.55-8.28 (8H, m); 9.20-9.80 (2H, m); 10.97 (1H, s); 10.86-11.63(1H, m)

MASS: 610 (M+1) (free)

Example 50-58)

mp: 180°-185° C.

α!_(D) ³⁰ : -21.3° (C=1.0, MeOH)

Example 51

The following piperazine derivatives (Table 2) were prepared by thesimilar manner to that of the each Example No. defined in the "Process"column. The physical properties of the object compounds are shown afterthe table. ##STR78##

                  TABLE 2    ______________________________________    Exam-                       Starting    ple   Object Compounds      Com-    No.   R.sup.4            Salt   pound  Process    ______________________________________    51-1)                             --     Pr. 8-2)                                           Ex. 1    51-2)           ##STR79##         HCl    Ex. 51-1)                                           Ex. 23    51-3)           ##STR80##         --     Ex. 51-6)                                           Ex. 11    51-4)           ##STR81##         HCl    Ex. 51-3)                                           Ex. 23    51-5)           ##STR82##         --     Ex. 51-6)                                           Ex. 16    51-6) H                  --     Ex. 51-1)                                           Ex. 6    51-7)           ##STR83##         HCl    Ex. 68 Ex. 23    51-8)           ##STR84##         --     Ex. 51-6)                                           Ex. 11    51-9)           ##STR85##         HCl    Ex. 51-8)                                           Ex. 23    51-10)           ##STR86##         --     Ex. 51-6)                                           Ex. 11    51-11)           ##STR87##         HCl    Ex. 51-10)                                           Ex. 23    ______________________________________

Physical properties of the compounds of the Example 51:

Example 51-1)

IR (Neat): 3020, 2910, 2810, 1638-1628, 1600 cm⁻¹

NMR (DMSO-d₆, δ): 1.87-4.78 (11H, m); 2.21 (6H, s); 6.36-7.46 (13H, m)

MASS: 399 (M+1)

Example 51-2)

IR (Nujol): 3370, 2600-2300, 1640-1628, 1598 cm⁻¹

NMR (DMSO-d₆, δ): 2.23 (6H, s); 2.76-5.07 (11H, m); 6.42-7.76 (13H, m);11.37 (1H, br s)

MASS: 399 (M+1) (free)

Example 51-3)

IR (Neat): 3430, 2920, 2800, 1624, 1600, 1507 cm⁻¹

NMR (DMSO-d₆, δ): 2.22 (6H, s); 1.94-4.80 (11H, m); 6.36-7.45 (12H, m)

MASS: 417 (M+1)

Example 51-4)

IR (Nujol): 3360, 2560, 1626, 1598, 1510 cm⁻¹

NMR (DMSO-d₆, δ): 2.23 (6H, s); 2.73-5.11 (11H, m);

6.40-7.90 (12H, m); 11.45 (1H, br s)

MASS: 417 (M+1) (free)

Example 51-5)

IR (Neat): 3450, 3020, 2990, 2920, 2860, 1637-1620, 1598 cm⁻¹

NMR (DMSO-d₆, δ): 2.21 (6H, m); 2.25-4.48 (13H, m); 6.11-7.45 (13H, m)

MASS: 441 (M+1)

Example 51-6)

IR (Neat): 3310, 2850-2800, 1620, 1596 cm⁻¹

NMR (DMSO-d₆, δ): 2.21 (6H, s); 2.50-4.90 (10H, m); 6.25-7.52 (8H, m)

MASS: 309 (M+1)

Example 51-7)

IR (Neat): 3380, 2930, 2410, 1633, 1599 cm ⁻¹

NMR (DMSO-d₆, δ): 2.21 (6H, s); 2.94-5.22 (13H, m); 6.32-7.52 (13H, m);11.34 (1H, br s)

MASS: 413 (M+1) (free)

Example 51-8)

IR (Neat): 2920, 2810, 1629, 1600 cm⁻¹

NMR (DMSO-d₆, δ): 2.21 (6H, s); 1.90-4.82 (9H, m); 3.48 (1H, d, J=13.3Hz); 3.78 (1H, d, J=13.0 Hz); 6.35-8.02 (15H, m)

MASS: 449 (M+1)

Example 51-9)

IR (Nujol): 3370, 2560, 1625 cm⁻¹

NMR (DMSO-d₆, δ): 2.22 (6H, s); 2.79-5.05 (11H, m); 6.41-8.24 (15H, m);11.47 (1H, br s)

MASS: 449 (M+1) (free)

Example 51-10)

IR (Neat): 3420, 2920, 2810, 1626, 1600 cm⁻¹

NMR (DMSO-d₆, δ): 2.21 (6H, s); 1.94-4.85 (11H, m); 6.32-7.20 (8H, m);8.06 (3H, s)

MASS: 535 (M+1)

Example 51-11)

IR (Neat): 3400, 2940, 2400, 1632, 1600 cm⁻¹

NMR (DMSO-d₆, δ): 2.24 (6H, s);. 2.78-5.11 (11H, m); 6.46-7.34 (8H, m);8.24 (1H, s); 8.50 (2H, s); 11.89 (1H, br s)

MASS: 535 (M+1) (free)

Example 52

The following piperazine derivatives (Table 3) were prepared by thesimilar manner to that of the each Example No. defined in the "Process"column. The physical properties of the object compounds are shown afterthe table. ##STR88##

                  TABLE 3    ______________________________________    Example   Object Compounds                             Starting    No.       R.sup.1    Salt    Compound Process    ______________________________________    52-1)     NO.sub.2   --      Pr. 17   Ex. 1    52-2)     NHCHO      --      Pr. 17   Ex. 1    52-3)                         --      Pr. 17   Ex. 1    52-4)     N(CH.sub.3).sub.2                         --      Pr. 17   Ex. 1    52-5)     NHSO.sub.2 CH.sub.3                         --      Ex. 52-6)                                          Ex. 40    52-6)     NHCOCH.sub.3                         --      Ex. 64   Ex. 40    52-7)     NHCH.sub.3 --      Ex. 52-3)                                          Ex. 64    ______________________________________

Physical properties of the compounds of the Example 52:

Example 52-1)

α!_(D) ¹⁸ : +8.7° (C=1.0, MeOH)

IR (Neat): 3260, 1635, 1540, 1420, 1310 cm⁻¹

NMR (DMSO-d₆, δ): 2.74-5.07 (11H, m); 6.57-8.59 (13H, m); 10.91(1H, s)

MASS: 563 (M+1)

Example 52-2)

α!_(D) ¹⁹ : -25.1° (C=1.0, MeOH)

IR (Neat): 3250, 1690, 1640, 1600, 1430, 1340-1270 cm⁻¹

NMR (DMSO-d₆, δ): 2.85-5.13 (11H, m); 6.57-8.44 (9H, m); 10.33-10.96(2H, m)

MASS: 561 (M+1)

Example 52-3)

α!_(D) ¹⁸ : -33.4° (C=1.0, MeOH)

IR (Neat): 3250, 1675, 1635, 1600, 1430 cm⁻¹

NMR (DMSO-d₆, δ): 2.89-5.13 (14H, m); 6.6-8.69 (14H, m); 10.86 (1H, s)

MASS: 575 (M+1)

Example 52-4)

α!_(D) ¹⁸ : +10.1° (C=1.0, MeOH)

IR (Neat): 3250, 1640, 1600, 1490, 1425 cm⁻¹

NMR (DMSO-d₆, δ): 2.83-5.14 (11H, m); 2.94 (6H, s); 6.52-7.84 (13H, m);10.85 (1H, s)

Example 52-5)

α!_(D) ¹⁸ : -43.7° (C=1.0, MeOH)

IR (Neat): 3400, 3250, 1640, 1600, 1430, 1330 cm⁻¹

NMR (DMSO-d₆, δ): 2.86-5.10 (11H, m); 3.0 (3H, s); 6.64-7.88 (12H, m);10.2-10.4 (1H, m); 10.85 (1H, s)

MASS: 611 (M+1)

Example 52-6)

α!_(D) ¹⁸ : -27.2° (C=1.0, MeOH)

IR (Neat): 3275, 1680, 1640, 1600, 1560, 1425 cm⁻¹

NMR (DMSO-d₆, δ): 2.08 (3H, s); 2.8-5.09 (11H, s); 6.6-8.11 (14H, m);10.83 (1H, s)

MASS: 575 (M+1)

Example 52-7)

IR (Neat): 3300, 1640, 1600, 1460, 1420 cm⁻¹

NMR (DMSO-d₆, δ): 2.64-5.1 (14H, m); 6.55-7.83 (14H, m); 10.85 (1H, s)

MASS: 547 (M+1)

Example 53

The following piperazine derivatives (Table 4) were prepared by thesimilar manner to that of the each Example No. defined in the "Process"column. The physical properties of the object compounds are shown afterthe table. ##STR89##

                  TABLE 4    ______________________________________    Ex-    am-                         Starting    ple  Object Compounds       Com-    No.  R.sup.4             Salt   pound  Process    ______________________________________    53-1)                             --     Ex. 53-4)                                           Ex. 16    53-2)          ##STR90##          HCl    Ex. 73 Ex. 23    53-3)          ##STR91##          --     Pr. 8-6)                                           Ex. 1    53-4)         H                   --     Ex. 53-3)                                           Ex. 6    53-5)         H                   HCl    Ex. 53-4)                                           Ex. 23    ______________________________________

Physical properties of the compounds of the Example 53:

Example 53-1)

α!_(D) ²⁰ : +2.57° (C=1.0, MeOH)

IR (Nujol): 1639, 1596, 1505 cm⁻¹

NMR (CDCl₃, δ): 2.13 (3H, s); 2.22 (3H, s); 2.55-5.39 (9H, m); 6.46-7.98(12H, m)

MASS: 593 (M+1)

Example 53-2)

α!_(D) ¹⁷ : +1.8° (C=1.0, MeOH)

IR (Nujol): 3380, 1635, 1607 cm⁻¹

NMR (DMSO-d₆, δ): 2.03, 2.08, 2.17 (6H, 3 s); 2.50-5.05 (9H, m); 5.53(1H, br s); 6.49-9.34 (12H, m)

MASS: 576 (M+1) (free)

Example 53-3)

IR (Neat): 3020, 2920, 2800, 2760, 1636 cm⁻¹

NMR (CDCl₃, δ): 2.20 (6H, s); 1.94-5.09 (11H, m); 6.45-7.90 (11H, m)

MASS: 535 (M+1)

Example 53-4)

IR (Neat): 3310, 2920, 1635-1627 cm⁻¹

NMR (CDCl₃, δ): 1.63 (1H, s); 2.22 (6H, s); 2.04-5.17 (9H, m); 6.54-7.88(6H, m)

MASS: 445 (M+1)

Example 53-5)

mp: >130° C. (C=1.0, MeOH)

α!_(D) ²⁰ : +31.27° (C=1.0, MeOH)

IR (Nujol): 3390, 1636 cm⁻¹

NMR (DMSO-d₆, δ): 2.11, 2.18(6H, 2 s); 2.62-4.66 (9H, m); 6.56-8.23 (6H,m); 9.61 (2H, m)

MASS: 445 (M+1) (free)

Example 54

The following piperazine derivatives (Table 5) were prepared by thesimilar manner to that of the each Example No. defined in the "Process"column. The physical properties of the object compounds are shown afterthe table. ##STR92##

                  TABLE 5    ______________________________________    Ex-    am-                         Starting    ple  Object Compounds       Com-    No.  R.sup.4             Salt   pound  Process    ______________________________________    54-1)                             --     Pr. 8-5)                                           Ex. 1    54-2)          ##STR93##          HCl    Ex. 54-1)                                           Ex. 23    54-3)         H                   --     Ex. 54-1)                                           Ex. 6    54-4)          ##STR94##          --     Ex. 69 Ex. 16    54-5)          ##STR95##          HCl    Ex. 54-3)                                           Ex. 11    ______________________________________

Physical properties of the compounds of the Example 54

Example 54-1)

IR (Neat): 3100-2700, 1635, 1490, 1430, 1380, 1350 cm⁻¹

NMR (CDCl₃, δ): 2.0-2.4 (2H, m); 2.8-3.8 (8H, m); 4.0-5.2 (1H, m);6.8-8.2 (13H, m)

MASS: 563 (M+1)

Example 54-2)

mp: 150°-165° C.

IR (Nujol): 3400, 2200-2700, 1635, 1440, 1360 cm⁻¹

NMR (DMSO-d₆, δ): 3.0-4.3 (9H,.m); 4.5-5.2 (2H, m); 6.9-7.3 (2H, m);7.4-8.3 (10H, m)

MASS: 563 (M+1) (free)

Example 54-3)

IR (Neat): 3300, 2700-3100, 1630, 1430, 1370, 1350 cm⁻¹

MASS: 473 (M+1)

Example 54-4)

mp: 60°-63° C.

α!_(D) ²³ : -25.2° (C=1.0, MeOH)

IR (Nujol): 1635, 1605, 1450, 1350, 1315 cm⁻¹

NMR (CDCl₃, δ): 2.8-5.4 (9H, m); 6.8-8.3 (15H, m)

MASS: 603 (M+1), 575, 473

Example 54-5)

mp: 124°-130° C. (dec.)

α!_(D) ²⁰ : +4.0° (C=0.05, MeOH)

IR (Nujol): 3300, 2300-2600, 1635, 1430, 1360 cm⁻¹

NMR (DMSO-d₆, δ): 2.0-2.3 (2H, m); 2.6-2.8 (2H, m); 3.0-4.0 (11H, m);4.2-5.3 (1H, m); 7.0-7.6 (9H, m); 7.8-8.4 (4H, m); 11.0-11.6 (1H, m)

MASS: 591 (M+1), 563

Example 55

The following piperazine derivatives (Table 6) were prepared by thesimilar manner to that of the each Example No. defined in the "Process"column. The physical properties of the object compounds are shown afterthe table. ##STR96##

                  TABLE 6    ______________________________________    Ex-    am-                         Starting    ple  Object Compounds       Com-    No.  R.sup.4             Salt   pound  Process    ______________________________________    55-1)                             --     Pr. 8-8)                                           Ex. 1    55-2)         H                   --     Ex. 55-1)                                           Ex. 6    55-3)          ##STR97##          --     Ex. 55-2)                                           Ex. 16    55-4)          ##STR98##          --     Ex. 55-2)                                           Ex. 16    55-5)          ##STR99##          --     Ex. 55-2)                                           Ex. 16    ______________________________________

Physical properties of the compounds of the Example 55

Example 55-1)

α!_(D) ¹⁹ : -43.2° (C=1.0, MeOH)

IR (Neat): 3400, 3300, 1630, 1440, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 1.09-1.32 (3H, m); 2.35-4.8 (10H, m); 6.53-8.45 (10H,m); 10.69 (1H, s)

MASS: 560 (M+1)

Example 55-2)

mp: 157°-159° C.

IR (Nujol): 3260, 1625, 1600, 1460, 1280 cm⁻¹

NMR (DMSO-d₆, δ): 9.3-1.18 (3H, m); 2.6-4.85 (8H, m); 6.65-8.4 (9H, m);10.86 (1H, s)

MASS: 470 (M+1)

Example 55-3)

α!_(D) ¹⁹ : -107.3° (C=1.0, MeOH)

IR (Neat): 3250, 1630, 1610, 1430, 1340, 1280 cm⁻¹

NMR (DMSO-d₆, δ): 0.86-1.4 (3H, m); 2.88-5.16 (10H, m); 6.6-8.86 (12H,m); 10.92 (1H, d, J=14 Hz)

MASS: 601 (M+1)

Example 55-4)

α!_(D) ¹⁸ : -127.1° (C=1.0, MeOH)

IR (Neat): 3260, 1630, 1595, 1510, 1420, 1340, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 0.9-1.4 (3H, m); 2.72-4.72 (10H, m); 6.86-8.27 (12H,m); 10.94 (1H, br s)

MASS: 618 (M+1)

Example 55-5)

α!_(D) ²⁰ : -107.5° (C=1.0, MeOH)

IR (Neat): 3260, 1680, 1625, 1425, 1350, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 0.9-1.2 (3H, m); 2.56 (3H, s); 2.7-4.9 (8H, m);6.86-8.2 (12H, m); 10.8 (1H, s)

MASS: 616 (M+1)

Example 56

The following piperazine derivatives (Table 7) were prepared by thesimilar manner to that of the each Example No. defined in the "Process"column. The physical properties of the object compounds are shown afterthe table. ##STR100##

                  TABLE 7    ______________________________________    Exam-    ple   Object Compounds     Starting    No.   R.sup.4           Salt   Compound                                           Process    ______________________________________    56-1)                            --     Pr. 8-9)                                           Ex. 1    56-2) H                 --     Ex. 56-1)                                           Ex. 6    56-3)           ##STR101##       --     Ex. 56-2)                                           Ex. 16    56-4) CH.sub.2 COOCH.sub.3                            --     Ex. 56-2)                                           Ex. 11    56-5) CH.sub.2 CONH.sub.2                            --     Ex. 56-4)                                           Ex. 9    ______________________________________

Physical properties of the compounds of the Example 56

Example 56-1)

α!_(D) ¹⁹ : -9.6° (C=1.0, MeOH)

IR (Neat): 3250, 1655, 1625, 1430, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 1.12 (3H, d, J=7 Hz); 2.35-4.82 (10H, m); 6.57-8.40(10H, m); 10.74 (1H, s)

MASS: 560 (M+1)

Example 56-2)

IR (Neat): 3250, 1620, 1430, 1350, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 1.13 (3H, s); 1.68-3.55 (8H, m); 4.46 (1H. br s);6.72-8.48 (8H, m); 10.86 (1H, s)

MASS: 470 (M+1)

Example 56-3):

α!_(D) ¹⁹ : +27.0° (C=1.0, MeOH)

IR (Neat): 3250, 1640, 1430, 1280 cm⁻¹

NMR (DMSO-d₆, δ): 1.1-1.4 (3H, m); 2.8-5.1 (10H, m); 6.6-8.94 (12H, m);10.90 (1H, d, J=14 Hz)

MASS: 601 (M+1)

Example 56-4)

IR (Neat): 3300, 1740, 1670, 1625, 1435, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 0.8-1.1 (3H, m); 2.6-4.8 (8H, m); 2.89 (3H, s); 3.70(2H, s); 6.44-8.56 (8H, m); 10.84 (1H, s)

MASS: 542 (M+1)

Example 56-5)

mp: 245°-247° C.

α!_(D) ¹⁸ : +3.1° (C=1.0, MeOH)

IR (Nujol): 3425, 3300, 3150, 1675, 1625, 1460, 1270 cm⁻¹

NMR (DMSO-d₆, δ): 0.8-1.1 (3H, m); 2.41-4.86 (10H, m); 6.57-8.22 (8H,m); 10.84 (1H, s)

MASS: 527 (M+1)

Example 57

The following piperazine derivatives (Table 8) were prepared by thesimilar manner to that of the each Example No. defined in the "Process"column. The physical properties of the object compounds are shown afterthe table. ##STR102##

                                      TABLE 8    __________________________________________________________________________    Example         Object Compounds      Starting    No.  R.sup.4            Salt                               Compound                                     Process    __________________________________________________________________________    57-1)                            -- Ex. 7-7)                                     Ex. 61    57-2)          ##STR103##        HCl                               Ex. 7-7)                                     Ex. 14    __________________________________________________________________________

Physical properties of the compounds of the Example 57

Example 57-1)

IR (Neat): 3380, 2960, 2920, 1678, 1634 cm⁻¹

NMR (DMSO-d₆, δ): 1.38, 1.42, 1.47 (9H, 3 s); 1.76-2.34 (2H, m);2.55-5.20 (14H, m); 6.86-8.31 (8H, m)

MASS: 630 (M+1)

Example 57-2)

mp: 206°-208° C.

α!_(D) ²² : -0.5° (C=10, MeOH)

IR (Nujol): 3600-3100, 2750-2100, 1641, 1274, 1134, 907 cm⁻¹

NMR (DMSO-d₆, δ): 0.80-1.00 (2H, m); 1.05-1.40 (6H, m); 1.60-1.95 (7H,m); 2.80-5.20 (11H, m); 6.90-7.70 (7H, m); 8.17-8.22 (1H, m)

MASS: 541 (M+1)

Example 58

The following piperazine derivatives (Table 9) were prepared by thesimilar manner to that of the each Example No. defined in the "Process"column. The physical properties of the object compounds are shown afterthe table. ##STR104##

                  TABLE 9    ______________________________________    Exam-    ple   Object Compounds     Starting    No.   R.sup.4           Salt   Compound                                           Process    ______________________________________    58-1)                            --     Ex. 7-8)                                           Ex. 20    58-2) CH.sub.2 CONH.sub.2                            --     Ex. 58-3)                                           Ex. 9    58-3) CH.sub.2 COOCH.sub.3                            --     Ex. 7-8)                                           Ex. 11    ______________________________________

Physical properties of the compounds of the Example 58

Example 58-1)

α!_(D) ²⁶ : +32.1° (C=1.0, MeOH)

IR (Film): 3275, 1635, 1430 cm⁻¹

NMR (DMSO-d₆, δ): 2.8-5.1 (9H, m); 6.6-8.2 (15H, m); 10.9 (1H, s)

MASS: 586 (M+1)

Example 58-2)

mp: >240° C.

α!_(D) ¹⁸ : +5.8° (C=1.0, MeOH)

IR (Nujol): 3440, 3300, 3150, 1675, 1625, 1460, 1270 cm⁻¹

NMR (DMSO-d₆, δ): 2.09-4.93 (11H, m); 6.67-8.24 (8H, m); 10.83 (1H, s)

MASS: 513 (M+1)

Example 58-3)

IR (Neat): 3300. 1740, 1625, 1435, 1275 cm⁻¹

NMR (DMSO-d₆, δ): 2.28-4.91 (9H, mn); 2.51 (3H, s); 3.64 (2H, s);6.6-8.2 (8H, m); 10.85 (1H, s)

MASS: 528 (M+1)

Example 59

The following piperazine derivatives (Table 10) were prepared by thesimilar manner to that of the each Example No. defined in the "Process"column. The physical properties of the object compounds are shown afterthe table. ##STR105##

                  TABLE 10    ______________________________________    Example Object Compounds Starting    No.     R.sup.4      Salt    Compound Process    ______________________________________    59-1)                         --      Pr. 8-4) Ex. 1    59-2)             ##STR106##  HCl     Ex. 59-1)                                          Ex. 23    59-3)   H            HCl     Ex. 59-1)                                          Ex. 69    ______________________________________

Physical properties of the compounds of the Example 59

Example 59-1)

IR (Neat): 3100-2700, 1635, 1470, 1430 cm⁻¹

NMR (CDCl₃, δ): 2.0-2.3 (2H, m); 2.6-3.8 (8H, m); 4.5-5.0 (1H, m);6.5-8.0 (11H, m)

MASS: 575 (M), 541

Example 59-2)

mp: 209°-211° C.

α!_(D) ²⁷ : +0.4° (C=1.0, MeOH)

IR (Nujol): 3400, 2600-2300, 1640, 1620, 1270 cm⁻¹

NMR (DMSO-d₆, δ): 2.8-5.1 (11H, m); 6.8-7.7 (9H, m); 7.8-7.9 (1H, m);8.2-8.3 (1H, m); 11.4-11.8 (1H, m)

MASS: 575 (M) (free)

Example 59-3)

mp: 245°-247° C.

α!_(D) ²⁴ : -9.6° (C=1.0, MeOH)

IR (Nujol): 3500, 2800-2500, 1650, 1610, 1590, 1450, 1360, 1330, 1310cm⁻¹

NMR (DMSO-d₆, δ): 2.6-5.2 (9H, m); 6.8-7.9 (5H, m); 8.21 (1H, s);9.4-10.2 (2H, m)

MASS: 485 (M) (free)

Example 60

The following piperazine derivatives (Table 11) were prepared by thesimilar manner to that of the each Example No. defined in the "Process"column. The physical properties of the object compounds are shown afterthe table.

                                      TABLE 11    __________________________________________________________________________    Example         Object Cmpounds                Starting    No.                              Salt                                        Compound                                              Process    __________________________________________________________________________    60-1)          ##STR107##                 -- Ex. 4-5)                                              Ex. 6    60-2)          ##STR108##                 -- Ex. 4-6)                                              Ex. 6    60-3)          ##STR109##                 -- Pr. 8-7)                                              Ex. 1    60-4)          ##STR110##                 HCl                                        Ex. 60-3)                                              Ex. 23    60-5)          ##STR111##                 -- Pr. 8-11)                                              Ex. 1    60-6)          ##STR112##                 HCl                                        Ex. 60-5)                                              Ex. 23    60-7)          ##STR113##                 2HCl                                        Ex. 7-1)                                              Ex. 14    60-8)          ##STR114##                 -- Pr. 8-10)                                              Ex. 61    __________________________________________________________________________

Physical properties of the compounds of the Example 60

Example 60-1)

IR (Nujol): 3200, 1620, 1610, 1320 cm⁻¹

NMR (DMSO-d₆, δ): 2.4-4.9 (9H, m); 6.7-8.1 (8H, m); 10.8 (1H, s); 10.87(1H, s)

MASS: 456 (M+1)

Example 60-2)

α!_(D) ²⁵ : +54.1° (C=1.0, MeOH)

IR (Film): 3250, 1620, 1430, 1340 cm⁻¹

NMR (DMSO-d₆, δ): 2.1-4.8 (9H, m); 6.3-8.3 (8H, m); 10.88 (1H, s); 10.93(1H, s)

MASS: 456 (M+1)

Example 60-3)

IR (Neat): 3100-2700 (m), 1640, 1440, 1380, 1350 cm⁻¹

NMR (CDCl₃, δ): 1.1-1.4 (3H, m); 1.6-1.8 (1H, m); 1.8-2.0 (1H, m);2.2-2.4 (1H, m); 2.7-3.0 (1H, m); 3.1-5.0 (6H, m); 3.61 (3H, s); 6.8-8.5(13H, m)

MASS: 574 (M+1)

Example 60-4)

mp: 130°-131° C. (dec.)

α!_(D) ²³ : -0.4° (C=0.5, MeOH)

IR (Nujol): 3350, 2700-2400, 1640, 1450, 1350 cm⁻¹

NMR (DMSO-d₆, δ): 1.0-1.4 (3H, m); 3.0-5.1 (10H, m); 3.65 (3H, s);6.6-8.5 (13H, m); 11.2-11.6 (1H, m)

Example 60-5)

IR (CHCl₃): 3450, 3060, 3020, 2940, 2860, 2800, 2760, 1628, 1600 cm⁻¹

NMR (DMSO-d₆, δ): 1.73 (2H, m); 1.85-2.05 (2H, m); 2.20 (6H, s);2.15-2.45 (2H, m); 2.60-3.50 (8H, m); 3.60-3.80, 4.25-4.45, 4.70-4.90(1H, m); 6.34, 6.71, 6.80-7.40 (13H, m)

MASS: 427 (M+1)

Example 60-6)

α!_(D) ²³ : -26.82° (C=1.0, CHCl₃)

IR (Nujol): 3370, 2380, 1625, 1598 cm⁻¹

NMR (DMSO-d₆, δ): 2.19, 2.24 (6H, s); 1.95-2.35 (2H, m); 2.55-2.75 (2H,m); 2.85-3.75, 3.85-4.05, 4.45-4.65, 4.95-5.15 (11H, m); 6.38, 6.71,6.80-7.45 (13H, m); 11.18 (1H, br s)

MASS: 427 (M+1) (free)

Example 60-7)

mp: 190°-210° C. (dec.)

α!_(D) ²⁰ : -14.6° (C=0.5, MeOH)

IR (Nujol): 2700-2200, 1630, 1500, 1350 cm⁻¹

NMR (DMSO-d₆, δ): 2.07, 2.17 (6H, 2 s); 2.8-5.4 (15H, m); 6.5-6.7 (1H,m), 6.8-7.2 (2H, m); 7.14 (1H, s); 7.54 (1H, s); 7.76 (1H, s); 8.20 (1H,s)

MASS: 557 (M+1) (free), 445

Example 60-8)

mp: 108°-109° C.

IR (Nujol): 1625, 1600, 1450, 1370, 1300 cm⁻¹

NMR (DMSO-d₆, δ): 2.0-3.6 (10H, m); 3.8-4.0 (1H, m); 6.8-7.8 (15H, m)

MASS: 449 (M+1)

Example 61

To a stirred mixture of 4-(dimethylamino)butyric acid hydrochloride (70mg) and 1-hydroxybenzotriazole hydrate (160 mg) in dichloromethane (10ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (80 mg) under ice cooling. After stirring for 30 minutes,a solution of (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine (200mg) in dichloromethane (5 ml) was added at the same temperature. Theresulting mixture was stirred for 2.5 hours at room temperature.Dichloromethane and aqueous sodium bicarbonate solution were added tothe reaction mixture and then the organic layer was separated and driedover magnesium sulfate. Evaporation of the solvent in vacuo gave (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-4-4-(dimethylamino)butyryl!-2-(1H-indol-3-yl-methyl)piperazine (0.25 g).

IR (Neat): 3270, 2920, 2860, 2820, 2770, 1630 cm⁻¹

NMR (DMSO-d₆, δ): 1.52-1.83 (2H, m); 2.09, 2.10, 2.13 (6H, 3 s);2.00-5.10 (13H, m); 6.53-8.25 (8H, m); 10.89 (1H, s)

MASS: 569 (M+1)

Example 62

Cyclohexyl isocyanate (0.06 ml) was added to a stirred solution of(2R)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)piperazine(0.2 g) in dichloromethane (10 ml) at room temperature. After stirringfor 4 hours, dichloromethane (10 ml) and water (5 ml) were added. Theorganic layer was separated, washed with brine and dried over magnesiumsulfate. After evaporation of the solvent in vacuo,.the residue waspurified by column chromatography on silica gel, eluting with a mixtureof dichloromethane and methanol (98:2) to give (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-4-cyclohexylcarbamoyl-2-(1H-indol-3-yl-methyl)piperazine(0.18 g).

IR (Neat): 3280, 2920, 2840, 1622, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.00-1.90 (10H, m); 2.76-4.90 (10H, m); 6.13-8.23 (9H,m); 10.87 (1H, s)

MASS: 581 (M+1)

Example 63

To a stirred solution of (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine (400mg) in dichloromethane (5 ml) was added 1,1'-carbonyldiimidazole (140mg) at room temperature. The resulting mixture was stirred overnight.Additional 1,1'-carbonyldiimidazole (70 mg) was added to the mixture andthen stirred for 1 hour. After the dichloromethane was removed underreduced pressure, N-methylpropylamine (1 g) was added. The mixture wasstirred at room temperature for 2 hours and then at reflux temperaturefor 12 hours. After cooling, dichloromethane and water were added to thereaction mixture. The organic layer was separated, washed with aqueous0.5N hydrochloric acid and brine. After evaporation of the solvent, theresidue was purified by column chromatography on silica gel, elutingwith a mixture of dichloromethane and methanol (99:1) to give (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(N-methyl-N-propylcarbamoyl)piperazine(0.18 g).

IR (Neat): 3260, 2950, 2910, 2850, 1628 cm⁻¹

NMR (DMSO-d₆, δ): 0.83 (3H, t, J=7.2 Hz); 1.38-1.67 (2H, m); 2.85 (3H,s); 2.69-5.04 (11H, m); 6.58-8.29 (8H, m).; 10.86 (1H, s)

MASS: 555 (M+1)

Example 64

A mixture of (2R)-4-(trans-cinnamoyl)-1-3-formylamino-5-(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazine(280 mg) and aqueous 10% hydrochloric acid (1 ml) in methanol (10 ml)was stirred at room temperature for 6 hours. The mixture was evaporatedunder reduced pressure. The resulting powder was collected by filtrationand dried to give (2R)-1-3-amino-5-(trifluoromethyl)-benzoyl!-4-(trans-cinnamoyl)-2-(1H-indol-3-yl-methyl)piperazinehydrochloride (280 mg).

α!_(D) ¹⁸ : -22.8° (C=1.0, MeOH)

IR (Neat): 3250, 2850, 2050, 1635, 1600, 1430, 1335 cm⁻¹

NMR (DMSO-d₆, δ): 2.78-5.54 (14H, m); 6.67-7.85 (13H, m); 10.89 (1H, s)

MASS: 533 (M+1) (free)

Example 65

Hydrochloric acid (0.22 ml) was added to a stirred mixture of (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-4-N-(2-hydroxybenzylidene)-2-aminoethyl!-2-(1H-indol-3-yl-methyl)piperazine(0.80 g), ethyl acetate (12 ml) and methanol (6 ml) at room temperature.The mixture was stirred at 50° C. for 4.5 hours and then concentrated invacuo to give an oil. The oil was treated with 4N hydrogen chloride indioxane solution (0.33 ml) to afford (2R)-4-(2-aminoethyl)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)piperazinedihydrochloride (0.57 g).

IR (Neat): 3340, 2930, 1625 cm⁻¹

NMR (DMSO-d₆, δ): 2.92-5.20 (13H, m); 6.48-8.85 (11H, m); 10.98 (1H, s);11.52-11.90 (1H, m)

MASS: 499 (M+1) (free)

Example 66

Sodium azide (0.21 g) was added to a stirred mixture of (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-4-(cyanomethyl)-2-(1H-indol-3-yl-methyl)piperazine(0.32 g) and ammonium chloride (0.17 g) in dimethylformamide (5 ml). Themixture was stirred at 115° C. for 16 hours. Additional sodium azide andammonium chloride were added to the reaction mixture until the startingmaterial was consumed. After cooling, the mixture was poured intoice-cold water. The resulting precipitate was collected by filtration,washed with water and dried. The precipitate was treated with 4Nhydrogen chloride in dioxane solution to give (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-4-(1H-tetrazol-5-yl-methyl)piperazinehydrochloride (0.19 g).

IR (Nujol): 3280, 2700-2300, 1635 cm⁻¹

NMR (DMSO-d₆, δ): 2.75-5.12 (11H, m); 6.54-8.30 (8H, m); 10.94 (1H, s)

MASS:.: 538 (M+1) (free)

Example 67

To a stirred mixture of (2R)-4-(3-aminopropyl)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-yl-methyl)-piperazine(0.20 g) and triethylamine (0.06 ml) in tetrahydrofuran (10 ml) wasadded 4-nitrophenyl chloroformate (0.08 g) under ice-cooling. After 35minutes, the resulting precipitate was filtered off. To the filtratewere added triethylamine (0.06 ml) and 30% methylamine in ethanol (0.05ml) at room temperature. After stirring for 1 hour and 40 minutes,additional 30% methylamine in ethanol (0.05 ml) was added to thereaction mixture and then stirred for 45 minutes. The reaction mixturewas concentrated in vacuo and the residue was partitioned betweendichloromethane and water. The organic layer was separated, washed withaqueous saturated sodium chloride solution and dried over magnesiumsulfate. After evaporation of the solvent in vacuo, the residue waspurified by column chromatography on silica gel eluting with a mixedsolvent of dichloromethane and methanol (100:3). The eluate was treatedwith 4N hydrogen chloride in dioxane solution to afford (2R)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-yl-methyl)-4-3-(3-methylureido)propyl!piperazine hydrochloride (0.08 g).

IR (Nujol): 3240, 2580, 1633 cm⁻¹

NMR (DMSO-d₆, δ): 1.72-2.03 (2H, m); 2.55, 2.56 (3H, 2 s); 2.92-5.21(15H, m); 6.60-8.29 (8H, m); 10.97 (1H, s); 11.12-11.45 (1H, m)

MASS: 570 (M+1) (free)

Example 68

Phenylacetaldehyde (80 mg) was added to a solution of(2R)-2-benzyl-1-(3,5-dimethylbenzoyl)piperazine (200 mg) in methanol (10ml) at room temperature and stirred for 4 hours. Sodium borohydride (20mg) was added to the reaction mixture under ice-cooling. The mixture wasstirred at room temperature for 5 hours and concentrated in vacuo. Theresidue was partitioned between dichloromethane and aqueous saturatedsodium bicarbonate solution. The organic layer was separated, washedwith brine and dried over magnesium sulfate. After evaporation of thesolvent in vacuo, the residue was purified on a silica gel columneluting with a mixture of toluene and ethyl acetate to give(2R)-2-benzyl-1-(3,5-dimethylbenzoyl)-4-(2-phenethyl)piperazine (70 mg).

IR (Neat): 3400, 3020, 2910, 2860, 2800, 1627-1592 cm⁻¹

NMR (DMSO-d₆, δ): 2.21 (6H, s); 1.84-4.88 (13H, m); 6.30-7.49 (13H, m)

MASS: 413 (M+1)

Example 69

To a stirred solution of (2R)-2-(benzob!thiophen-3-yl-methyl)-4-benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-piperazine (0.75 g) in dichloromethane(8 ml) was added dropwise 1-chloroethyl chloroformate (0.19 ml) atice-bath temperature. The resulting mixture was stirred at roomtemperature for 1 hour and then at reflux temperature for 5 hours. Thereaction mixture was evaporated under reduced pressure. Methanol (5 ml)was added to the residue and the whole mixture was heated underrefluxing for 1 hour. The mixture was concentrated in vacuo and theresidue was partitioned between aqueous sodium bicarbonate solution (10ml) and ethyl acetate (20 ml). The organic layer was separated, washedwith brine and dried over magnesium sulfate. After evaporation of thesolvent in vacuo, the residue was treated with 4N hydrogen chloride inethyl acetate solution to afford (2R)-2-(benzob!thiophen-3-yl-methyl)-1- 3,5-bis(trifluoromethyl)benzoyl!piperazinehydrochloride (0.69 g).

mp: 145°-155° C.

α!_(D) ²⁴ : +5.38° (C=0.13, MeOH)

IR (Nujol): 3300, 2900-2400, 1625, 1430, 1350 cm⁻¹

NMR (DMSO-d₆, δ): 3.0-4.0 (9H, m); 4.2-4.3 (1H, m); 7.0-8.4 (8H, m);9.5-10.2 (1H, m)

MASS: 473 (M+1) (free)

Example 70

To a solution of (2R)-2-benzyl-1- 3,5-bis(trifluoromethyl)benzoyl!-4-(4R)-4-hydroxy-1-tert-butoxycarbonyl-L-propyl!piperazine (0.68 g) indichloromethane (10 ml) was added 4N hydrogen chloride in dioxanesolution (10 ml) at 0° C. The resulting mixture was stirred at the sametemperature for 1 hour and then concentrated under reduced pressure. Theresidue was pulverized with ethyl ether, collected by filtration andwashed with ethyl ether to give (2R)-2-benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4- (4R)-4-hydroxy-L-propyl!piperazinehydrochloride (0.57 g).

mp: 234°-236° C.

IR (Nujol): 3300,1635 cm⁻¹

NMR (DMSO-d₆, δ): 1.83-2.73 (2H, m); 2.79-5.23 (13H, m); 5.52, 5.65 (1H,2 br s); 6.84-8.25 (8H, m); 8.80 (1H, br s); 10.00 (1H, br s)

MASS: 530 (M+1) (free)

Example 71

(2R)-2-Benzyl-1 3,5-bis(trifluoromethyl)benzoyl!-4-(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl-carbonyl)-L-propyl!piperazine(0.21 g) was obtained from (2R)-2-benzyl-1-3,5-bis(trifluoromethyl)benzoyl!-4- (4R)-4-hydroxy-L-propyl!piperazinehydrochloride (300 mg) and 1-methyl-1H-indole-3-carboxylic acid (90 mg)by a similar manner to that of Example 61.

mp: >150° C.

IR (Nujol): 3330, 1633, 1527 cm⁻¹

NMR (DMSO-d₆, δ): 1.85-2.28 (2H, m); 2.52-5.46 (14H, m); 3.86 (3H, s);6.88-8.32 (13H, m)

MASS: 687 (M+1)

Example 72

To a mixture of (2R)-1-3,5-bis(trifluoromethyl)-benzoyl!-4-(3-carboxypropyl)-2-(1H-indol-3-yl-methyl)-piperazine(180 mg), 4-piperidinopiperidine (56 mg) and 1-hydroxybenzotriazolehydrate (45 mg) in dichloromethane (4 ml) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (64 mg) atice-bath temperature. After stirring for 30 minutes, the reactionmixture was allowed to warm to room temperature and was stirred for 2hours and 40 minutes. The reaction mixture was concentrated underreduced pressure and the resulting residue was partitioned between ethylacetate and water. The organic layer was washed successively withaqueous saturated sodium bicarbonate and brine, and dried over magnesiumsulfate. After evaporation of the solvent, the residue was purified bycolumn chromatography on silica gel eluting with a mixture ofdichloro-methane and methanol (10:1) to give (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-4-3-(4,1'-bipiperidin-1-yl-carbonyl)-propyl!-2-(1H-indol-3-yl-methyl)piperazine,which was converted to the corresponding dihydrochloride salt (0.18 g)by treatment with 4N hydrogen chloride in dioxane solution.

IR (Nujol): 3350, 2630, 1626 cm⁻¹

NMR (DMSO-d₆, δ): 1.17-2.24 (12H, m); 2.34-5.22 (22H, m); 6.57-8.29 (8H,m); 10.22-10.60 (1H, m); 10.97 (1H, s); 10.83-11.57 (1H, m)

MASS: 692 (M+1) (free)

Example 73

To a stirred mixture of trans-3-(3-pyridyl)acrylic acid (100 mg) andtriethylamine (0.19 ml) in dichloromethane (10 ml) was added 1-naphthoylchloride (0.1 ml) at -15° C. After stirring for 30 minutes, a solutionof (2S)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)piperazine (300mg) in dichloromethane (10 ml) was added at -15° C. and the resultingmixture was stirred for 30 minutes at the same temperature and then for1 hour at room temperature. Dichloromethane and water were added to thereaction mixture and the organic layer was separated, washedsuccessively with aqueous saturated sodium bicarbonate solution, water,0.5N hydrochloric acid and brine, and dried over magnesium sulfate.After evaporation of the solvent in vacuo, the residue was purified on asilica gel column (20 g) eluting with a mixture of dichloromethane andmethanol (100:2)to give (2S)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(3,4-dimethylbenzyl)-4-(3-(3-pyridyl)-trans-acryloyl!piperazine (0.34 g).

IR (Nujol): 3430, 1637, 1607 cm⁻¹

NMR (CDCl₃, 8): 2.13, 2.22 (6H, 2 s); 2.60-5.38 (9H, m); 6.45-8.91 (12H,m)

MASS: 576 (M+1)

Example 74

A mixture of (2R)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-ylmethyl)piperazine (1.5g), benzyl 2-bromoacetate (0.79 g), triethylamine (0.55 ml) andtetrahydrofuran (15 ml) was stirred overnight at room temperature. Theresulting insoluble material was removed by filtration and the filtratewas concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel eluting with a mixture ofdichloromethane and methanol (30:1) to give(2R)-4-(benzyloxycarbonylmethyl)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-ylmethyl)piperazine(1.92 g).

α!_(D) ²¹ : -11.6 (C=1.0, MeOH)

IR (Neat): 3600-3100, 1735, 1626, 1275, 1129, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.20-5.20 (13H, m); 6.60-8.20 (13H, m); 10.85 (1H, brs)

MASS: 604 (M+1), 454

Example 75

A mixture of (2R)-4-(benzyloxycarbonylmethyl)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-ylmethyl)-piperazine(1.86 g), 10% Pd charcoal (0.186 g) and tetrahydrofuran (93 ml) wasstirred for 17 hours under hydrogen gas atmosphere (1 atm). The catalystwas removed by filtration and the filtrate was concentrated. The residuewas triturated with ethyl ether to give (2R)-4-(carboxymethyl)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-ylmethyl)piperazine (0.83g) as a white powder.

α!_(D) ¹⁹ : -3.0° (C=0.5, DMF)

mp: 152°-156° C.

IR (Nujol): 3600 -3100, 1654, 1630, 1277, 1196, 1130 cm⁻¹

NMR (DMSO-d₆, δ): 2.20-5.20 (11H, m); 6.60-8.20 (8H, m); 10.85 (1H, s)

MASS: 514 (M+1)

Example 76

To a stirred solution of (2R)-4-(carboxymethyl)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-ylmethyl)-piperazine (1g) in dry dimethylformamide (10 ml) was added 1-hydroxybenzotriazole(0.29 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.41 g) at room temperature. After stirring for 15 minutes at roomtemperature, 1-amino-4-methylpiperazine (320 mg) was added and furtherstirred for 5 hours at the same temperature. The reaction mixture waspoured into a solution of sodium hydrogencarbonate (1.8 g) in water (100ml) and extracted three times with 20 ml portions of ethyl acetate. Theorganic layers were combined and washed with brine (30 ml). The organiclayer was dried over magnesium sulfate and filtered and the solvent wasremoved by rotary evaporator. The crude product was purified bychromatography (silica gel, dichloromethane:methanol, 5:1) to afford(2R)-1- 3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-ylmethyl)-4-N-(4-methyl-1-piperazinyl)carbamoylmethyl!piperazine (0.94 g) as ayellowish powder.

IR (Nujol): 3180, 1680, 1630, 1276, 1170, 1130, 1005, 897 cm⁻¹

NMR (DMSO-d₆, δ): 2.16 (3H, s); 2.0-5.0 (19H, m); 6.6-8.2 (8H, m), 8.47,8.77 (1H, 2 s); 10.85 (1H, s)

Example 77

(2R)-1- 3,5-Bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-ylmethyl)-4-N-(4-methyl-1-piperazinyl)carbamoylmethyl!-piperazine (10.89 g) andfumaric acid (2.07 g) were dissolved in ethanol (50 ml) at 70° C. Aftercooling, the resulting solution was concentrated under reduced pressureto give a powder (13.18 g). The powder (9.68 g) was dissolved in2-butanone (194 ml) at reflux temperature and the solution was allowedto stir at room temperature to afford crystals, which was collected byfiltration and dried to give fumarate salt of (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-ylmethyl)-4-N-(4-methyl-1-piperazinyl)carbamoylmethyl!piperazine (7.94 g).

mp: 169.5°-171° C.

IR (Nujol): 3220, 1700, 1653, 1630, 1275, 1217, 1168, 1122, 979, 894,730 cm⁻¹

NMR (DMSO-d₆, δ): 2.23, 2.26 (3H, 2 s); 2.10-4.93 (19H, m); 6.60 (2H,s); 6.54-8.23 (8H, m); 8.50, 8.85 (1H, 2 s); 10.85 (1H, s)

Example 78

A mixture of (2R)-1-3,5-bis(trifluoromethyl)-benzoyl!-2-(1H-indol-3-ylmethyl)piperazine (120mg), 4-chloromethyl-2-(2-methoxyethylcarbonylamino)thiazole (70 mg) andpowdered sodium hydrogen carbonate (27 mg) in dry dimethylformamide wasstirred for 5 hours and 20 minutes at 60° C. The reaction mixture waspowered into water and the resulting precipitate was collected byfiltration. The crude product was purified by column chromatography onsilica gel eluting with a mixture of dichloromethane and methanol(30:1). The eluate was evaporated under reduced pressure and treatedwith 17.6% hydrogen chloride in ethanol (0.12 ml) to give (2R)-1-3,5-bis(trifluoromethyl)benzoyl!-2-(1H-indol-3-ylmethyl)-4-2-(3-methoxypropanoylamino)thiazol-4-yl!methyl!piperazine hydrochloride(140 mg).

α!_(D) ²² : -34.0° (C=0.5, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1635, 1275, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.60-5.20 (18H, m); 6.60-8.21 (9H, m); 10.90-11.00(1H, m); 11.20-12.00 (1H, m); 12.19 (1H, s)

MASS: 654 (M+1) (free)

Example 79

The following piperazine derivatives (Table 12) were prepared by thesimilar manner to that of the each Example No. defined in the "Process"column. The physical properties of the object compounds are shown afterthe table. ##STR115##

                                      TABLE 12    __________________________________________________________________________    Example         Object Compounds      Starting    No.  R.sup.4            Salt                               Compound                                     Process    __________________________________________________________________________    79-1)                            HCl                               Ex. 6 Ex. 78    79-2)          ##STR116##        HCl                               Ex. 6 Ex. 78    79-3)          ##STR117##        HCl                               Ex. 6 Ex. 78    79-4)          ##STR118##        HCl                               Ex. 6 Ex. 78    79-5)          ##STR119##        HCl                               Ex. 6 Ex. 78    79-6)          ##STR120##        HCl                               Ex. 6 Ex. 78    79-7)          ##STR121##        HCl                               Ex. 6 Ex. 78    79-8)          ##STR122##        HCl                               Ex. 6 Ex. 78    79-9)          ##STR123##        2HCl                               Ex. 6 Ex. 78    79-10)          ##STR124##        HCl                               Ex. 6 Ex. 78    79-11)          ##STR125##        -- Ex. 6 Ex. 14    79-12)          ##STR126##        2HCl                               Ex. 79-11)                                     Ex. 23    79-13)          ##STR127##        HCl                               Ex.79-11)                                     Ex. 40    79-14)          ##STR128##        -- Ex. 6 Ex. 16    79-15)          ##STR129##        HCl                               Ex. 6 Ex. 78    79-16)          ##STR130##        HCl                               Ex. 6 Ex. 78    __________________________________________________________________________

Physical properties of the compounds of the Example 79:

Example 79-1)

α!_(D) ²⁴ : 30.2° (C=0.5, MeOH)

mp: 185°-189° C.

IR (Nujol): 3660-3100, 2800-2000, 1635, 1545, 1276, 1183, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.36-5.10 (14H, m); 6.59-8.22 (10H, m); 10.90-11.00(1H, m); 12.15 (1H, s)

MASS: 610 (M+1) (free),456

Example 79-2)

α!_(D) ²² : -33.4° (C=0.5, MeOH)

IR (Nujol): 3650-3100, 2800-2000, 1715, 1635, 1555, 1274, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.25 (3H, t, J=7.1 Hz); 2.73-5.10 (13H, m); 6.60-8.30(9H, m); 10.90-11.00 (1H, m); 11.81 (1H, br s)

MASS: 640 (M+1) (free), 456

Example 79-3)

α!_(D) ²² : -42.0° (C=0.5, MeOH)

IR (Nujol): 3600-3100, 2750-2000, 1635, 1540, 1277, 1175, 1130 cm⁻¹

NMR (DMSO-d₆, δ): 2.73-5.20 (11H, m); 6.59-8.21 (14H, m); 10.90-11.00(1H, m); 12.69 (1H, s)

MASS: 672 (M+1) (free), 456

Example 79-4)

α!_(D) ²² : -24.2° (C=0.5, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1635, 1540, 1276, 1170, 1129, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.23 (9H, s); 2.73-5.10 (11H, m); 6.50-8.20 (9H, m);10.80-11.00 (1H, m); 11.84 (1H, s)

MASS: 652 (M+1) (free), 456

Example 79-5)

α!_(D) ²² : -35.8° (C=0.5, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1635, 1540, 1276, 1170, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 0.80-1.00 (4H, m); 1.90-2.00 (1H, m); 2.73-5.15 (11H,m); 6.60-8.21 (9H, m); 10.90-11.00 (1H, m); 12.43 (1H, m)

MASS: 636 (M+1) (free), 456

Example 79-6)

α!_(D) ²² : -30.4° (C=0.5, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1635, 1542, 1275, 1170, 1131, 900 cm⁻¹

NMR (DMSO-d₆, δ): 0.89 (3H, t, J=7.4 Hz); 1.56-1.67 (2H, m); 2.40-2.50(2H, m); 2.73-5.15 (11H, m); 6.56-8.21 (9H, m); 10.90-10.94 (1H, m);12.12 (1H, s)

MASS: 638 (M+1) (free)

Example 79-7)

α!_(D) ²² : -34.0° (C=0.5, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1635, 1543, 1277, 1170, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.08 (3H, t, J=7.4 Hz), 2.43-2.50 (2H, m); 2.73-5.15(11H, m); 6.55-8.21 (9H, m); 10.90-10.94 (1H, m); 12.11 (1H, s)

MASS: 624 (M+1) (free)

Example 79-8)

α!_(D) ²² : -15.2° (C=0.5, MeOH)

IR (Nujol): 3600-3100, 2750-2000, 1635, 1278, 1172, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.73-5.20 (11H, m); 6.60-8.52 (11H, m); 10.94 (1H, s)

MASS: 596 (M+1) (free), 456

Example 79-9)

α!_(D) ²² : -20.6° (C=0.5, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1635, 1276, 1170, 1129, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.09 (3H, s); 2.73-5.20 (11H, m); 6.60-8.20 (11H, m);10.46 (1H, s); 10.91 (1H, s)

MASS: 604 (M+1) (free)

Example 79-10)

α!_(D) ²² : -13.0° (C=0.5, MeOH)

IR (Nujol): 3650-3050, 2750-2000, 1685, 1636, 1524, 1275, 1130, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.31 (3H, t, J=6.5 Hz), 2.24 (3H, s); 2.73-5.20 (13H,m); 6.66-8.25 (8H, m); 10.94 (1H, s); 12.71 (1H, s)

MASS: 682 (M+1) (free)

Example 79-11)

α!_(D) ²² : -20.8° (C=0.5, MeOH)

IR (Neat): 3700-3000, 1615, 1515, 1272, 1125, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.00-5.00 (13H, m); 6.38-8.20 (9H, m); 10.80 (1H, s)

MASS: 568 (M+1), 456

Example 79-12)

α!_(D) ²² : -10.4° (C=0.5, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1635, 1277, 1130 cm⁻¹

NMR (DMSO-d₆, δ): 3.00-5.20 (11H, m); 6.60-8.30 (11H, m); 10.95 (1H, s)

MASS: 568 (M+1) (free), 456

Example 79-13)

α!_(D) ²² : -31.8° (C=0.5, MeOH)

IR (Nujol): 3270, 2750-2000, 1637, 1531, 1279, 1124, 964 cm⁻¹

NMR (DMSO-d₆, δ): 2.73-5.15 (14H, m); 6.60-8.25 (10H, m); 10.89 (1H, s)

MASS: 646 (M+1) (free), 568, 456

Example 79-14)

α!_(D) ²² : 11.8° (C=0.5, MeOH)

IR (Nujol): 3650-3100, 1625, 1543, 1275, 1130 cm⁻¹

NMR (DMSO-d₆, δ): 2.09-2.11 (3H, m); 2.52-5.00 (11H, m); 6.63-8.20 (9H,m); 10.85 (1H, s); 12.07 (1H, s)

MASS: 638 (M+1), 456

Example 79-15)

α!_(D) ²² : -51.60 (C=0.5, MeOH)

IR (Nujol): 3650-3100, 2750-2000, 1634, 1540, 1274, 1170, 1127, 900 cm⁻¹

NMR (DMSO-d₆, δ): 2.31 (3H, s); 2.73-5.35 (11H, m); 6.63-8.25 (8H, m);10.94-11.00 (1H, m); 13.20 (1H, s)

MASS: 611 (M+1) (free)

Example 79-16)

α!_(D) ²² : -23.4° (C=0.5, MeOH)

IR (Nujol): 3650-3000, 2750-2000, 1620, 1274, 1175, 1128, 900 cm⁻¹

NMR (DMSO-d₆, δ): 1.10 (3H, t, J=7.2 Hz); 2.60-5.10 (16H, m); 6.50-8.21(9H, m); 10.91 (1H, s); 11.50-11.90 (1H, br s)

MASS: 638 (M+1) (free)

What we claim is:
 1. A compound of the formula: ##STR131## wherein R⁴ isa group of the formula --A-Z, wherein A is a direct bond, wherein Z isselected from the group consisting of ##STR132## or a pharmaceuticallyacceptable salt thereof. 2.(2R)-1-(3,5-Bis-(trifluoromethyl)benzoyl)-2-(1H-indol-3-ylmethyl)-4-((N-(4-methyl-1-piperazinyl)carbamoylmethyl)-piperazinefumarate.
 3. A method for treating or preventing asthma, which comprisesadministering an effective amount of a compound of claim 1 or 2 to ahuman being or an animal in need thereof.
 4. A pharmaceuticalcomposition, comprising the compound of claim 1 or 2 as an activeingredient, in association with a pharmaceutically acceptable carrier.